Circadian Pharmacokinetics [1 ed.] 9789811588068, 9789811588075

Table of contents :
Preface
Contents
Chapter 1: Introduction to Mammalian Circadian Clock System
1.1 Introduction
1.2 Circadian Rhythms
1.3 Molecular Basis of Mammalian Circadian Clock
1.4 Clock Genes
1.4.1 CLOCK, BMAL1, and NPAS2
1.4.2 PERs and CRYs
1.4.3 REV-ERBs and RORs
1.4.4 PAR bZip Proteins (DBP, HLF, and TEF) and E4BP4
1.5 Circadian Clock and Human Health
References
Chapter 2: Introduction to Pharmacokinetics
2.1 ADME Processes and Pharmacokinetics
2.2 Drug Absorption
2.2.1 Gastrointestinal Absorption
2.2.2 Enterohepatic Recycling
2.2.3 Bioavailability
2.3 Drug Distribution
2.3.1 Volume of Distribution
2.3.2 Tissue Barriers to Distribution
2.3.3 Protein Binding
2.4 Drug Metabolism
2.4.1 Phase I and Phase II Reactions
2.4.2 Hepatic Clearance
2.4.3 Factors Affecting Drug Metabolism
2.5 Drug Excretion
2.5.1 Renal Excretion
2.5.2 Transporters Involved in Renal Secretion and Reabsorption
2.5.3 Biliary Excretion
2.5.4 Transporters Involved in Biliary Excretion
2.6 Drug Concentration-Time Profile
2.7 Time-Dependent Pharmacokinetics
References
Chapter 3: Circadian Clock and Metabolic Diseases
3.1 Introduction
3.2 Role of Circadian Clock in Metabolic Diseases
3.2.1 Circadian Clock and Glucose Metabolism
3.2.2 Circadian Clock and Lipid Metabolism
3.2.3 Circadian Clock and Cholesterol Metabolism
3.2.4 Circadian Clock and Amino Acid Metabolism
3.2.5 Circadian Clock and Bilirubin Metabolism
3.2.6 Circadian Clock and Bone Metabolism
3.2.7 Targeting Clock Genes to Treat Metabolic Diseases
3.3 Feedback of Metabolism on the Circadian Clock
3.3.1 Metabolic Diseases Lead to Circadian Dysfunction
3.3.2 Metabolic Signals Act as Synchronization Cues (Zeitgebers)
3.4 Concluding Remarks
References
Chapter 4: Circadian Clock and CYP Metabolism
4.1 Introduction
4.2 CYP Superfamily
4.3 Diurnal Expression of CYP Enzymes
4.4 Circadian Regulation of CYP Expression and Activity
4.4.1 CYP1A1
4.4.2 CYP1A2
4.4.3 CYP2A4/5
4.4.4 CYP2B10
4.4.5 CYP2E1
4.4.6 CYP3A11
4.4.7 CYP4A10/14
4.4.8 CYP7A1
4.4.9 CYP8B1
4.4.10 CYP11A1
4.5 Effects of CYPs on Circadian Clock
4.6 Concluding Remarks
References
Chapter 5: Circadian Clock and Non-CYP Phase I Metabolism
5.1 Introduction
5.2 Mammalian Circadian Clock System
5.3 Mammalian Non-CYP Phase I Enzymes and Their Functions
5.3.1 FMOs
5.3.2 AOs and XOs
5.3.3 CES
5.3.4 ADHs and ALDHs
5.3.5 MAOs
5.4 Role of Non-CYP Enzymes in Drug Metabolism
5.4.1 FMOs and Drug Metabolism
5.4.2 AOs/XOs and Drug Metabolism
5.4.3 CES and Drug Metabolism
5.4.4 ADHs/ALDHs and Drug Metabolism
5.4.5 MAOs and Drug Metabolism
5.5 Diurnal Expression of Non-CYP Phase I Enzymes
5.5.1 Circadian Rhythm in FMO Expression
5.5.2 Circadian Rhythm in AO and XO Expression
5.5.3 Circadian Rhythm in CES Expression
5.5.4 Circadian Rhythm in ADH/ALDH Expression
5.5.5 Circadian Rhythm in MAO Expression
5.6 Regulation of Non-CYP Phase I Enzymes by Circadian Clock
5.7 Concluding Remarks
References
Chapter 6: Circadian Clock and Phase II Metabolism
6.1 Introduction
6.2 Circadian Clock and Glucuronidation
6.2.1 Glucuronidation and UGTs
6.2.2 Circadian Rhythms in UGTs
6.2.3 Regulation of UGTs by Circadian Clock
6.3 Circadian Clock and Sulfation
6.3.1 Sulfation and SULTs
6.3.2 Circadian Rhythms in SULTs
6.3.3 Regulation of SULTs by Circadian Clock
6.4 Circadian Clock and Glutathione Conjugation
6.4.1 Glutathione Conjugation and GSTs
6.4.2 Circadian Rhythms in GSTs
6.4.3 Regulation of GSTs by Circadian Clock
6.5 Circadian Clock and Acetylation
6.5.1 Acetylation and NATs
6.5.2 Circadian Rhythms in NATs
6.5.3 Regulation of AA-NAT by Circadian Clock
6.6 Concluding Remarks
References
Chapter 7: Circadian Clock and Uptake Transporters
7.1 Introduction
7.2 Mammalian Drug Uptake Transporters
7.3 Role of Uptake Transporters in Drug Pharmacokinetics
7.3.1 Role of OATPs in Drug Pharmacokinetics
7.3.2 Role of OCTs in Drug Pharmacokinetics
7.3.3 Role of OATs in Drug Pharmacokinetics
7.4 Diurnal Expression and Activity of Uptake Transporters
7.4.1 OATPs
7.4.2 OCTs
7.4.3 OATs
7.4.4 PEPT1
7.4.5 OCTNs
7.4.6 ABST and NTCP
7.4.7 MCTs
7.4.8 Hexose Transporters
7.4.9 NPTs
7.4.10 SLC19A1
7.5 Regulation of Uptake Transporters by Circadian Clock Components
7.5.1 OATPs
7.5.2 OCTs
7.5.3 OATs
7.5.4 PEPT1
7.5.5 OCTN1
7.5.6 MCTs
7.5.7 Hexose Transporters
7.6 Concluding Remarks
References
Chapter 8: Circadian Clock and Efflux Transporters
8.1 Introduction
8.2 Mammalian Drug Efflux Transporters
8.2.1 P-Glycoprotein/ABCB1
8.2.2 MRPs/ABCCs
8.2.3 BCRP/ABCG2
8.2.4 BSEP/ABCB11
8.2.5 MATEs/SLC47As
8.3 Diurnal Expression and Activity of Efflux Transporters
8.3.1 P-gp
8.3.2 MRPs
8.3.3 BCRP
8.3.4 BSEP
8.3.5 MATEs
8.4 Regulation of Efflux Transporters by Circadian Clock
8.4.1 P-gp
8.4.2 MRPs
8.4.3 BCRP
8.4.4 BSEP
8.4.5 MATEs
8.5 Concluding Remarks
References
Chapter 9: Role of Pharmacokinetics in Chronotherapeutics
9.1 Introduction
9.2 Molecular Basis of Circadian Rhythms
9.3 Chronopharmacokinetics: Pharmacokinetic Outcome of Circadian Rhythms
9.3.1 Clinical Evidence
9.3.2 Evidence from Experimental Animals
9.4 Mechanisms of Chronopharmacokinetics
9.4.1 Circadian Variations in Drug Absorption
9.4.2 Circadian Variations in Drug Distribution
9.4.3 Circadian Variations in Drug Metabolism
9.4.4 Circadian Variations in Drug Excretion
9.5 Pharmacokinetics-Based Chronotherapeutics
9.5.1 Acetaminophen
9.5.2 Cisplatin
9.5.3 Cyclophosphamide
9.5.4 Doxorubicin
9.5.5 Gentamicin
9.5.6 Methotrexate
9.5.7 Morphine
9.5.8 Theophylline
9.5.9 Traditional Chinese Medicines (TCMs)
9.5.10 Valproate
9.6 Chrono-Drug Delivery Systems
9.6.1 CEFORM
9.6.2 CHRONOTOPIC
9.6.3 CODAS
9.6.4 CONTINR
9.6.5 DIFFUCAPS
9.6.6 EGALET
9.6.7 GeoClock
9.6.8 OROS
9.6.9 PORT
9.6.10 TIMERx
9.6.11 Controlled-Release Microchip
9.6.12 Chrono-modulating Infusion Pumps
9.6.13 Three-Dimensional Printing
9.6.14 Physicochemical Modification of API
9.7 Concluding Remarks
References
Chapter 10: Role of Non-Pharmacokinetic Factors in Chronoefficacy
10.1 Introduction
10.2 Drugs with Chronoefficacy
10.2.1 Drugs for Cancers
5-FU
Erlotinib
Roscovitine
10.2.2 Drugs for Inflammation Diseases
Berberine
Prednisone
Indomethacin
10.2.3 Drugs for Metabolic Diseases
Amlodipine
Pregabalin
Isosorbide Dinitrate
Insulin Glargine
10.2.4 Drugs for Nervous and Mental Diseases
Diazepam
Propofol
10.3 Drug Target-Based Chronoefficacy
10.3.1 Clock Proteins as Drug Targets
REV-ERBα
10.3.2 Non-Clock Circadian Proteins as Drug Targets
Methionine Aminopeptidase 2 (MetAP2)
Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2)
Calcium Channel a2δ-1 Subunit
5-Hydroxytryptamine (5-HT)
Interferon-α (IFN-α) Receptor
Platelet-Derived Growth Factor (PDGF) Receptors
Coagulation Factor (FX)
10.4 Rhythmic Disease-Based Chronoefficacy
10.5 Concluding Remarks
References

Citation preview

Baojian Wu Danyi Lu Dong Dong  Editors

Circadian Pharmacokinetics

Circadian Pharmacokinetics

Baojian Wu • Danyi Lu • Dong Dong Editors

Circadian Pharmacokinetics

Editors Baojian Wu Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy Jinan University Guangzhou, China

Danyi Lu Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy Jinan University Guangzhou, China

Dong Dong School of Medicine Jinan University Guangzhou, China

ISBN 978-981-15-8806-8 ISBN 978-981-15-8807-5 https://doi.org/10.1007/978-981-15-8807-5

(eBook)

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are solely and exclusively licenced by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Preface

Pharmacokinetics deals with the in vivo fate of or disposition processes of the drug (i.e. how the body does to the drug) that determine drug exposure and therefore pharmacological effects. In general, drug molecules undergo four main disposition processes in the body, namely absorption, distribution, metabolism, and excretion (ADME; the so-called four components of pharmacokinetics). Pharmacokinetic study is an integral part of drug research and development because (1) pharmacokinetic data are critical in the formulation of drug dosing regimen and (2) pharmacokinetic property is a key determinant to the success of drug development. Poor pharmacokinetic property (e.g. poor absorption, fast clearance, and formation of toxic metabolite) is reported to be one of the main causes of drug attrition. It has long been recognized that dosing time accounts for variability in drug effect (up to a tenfold magnitude). Dosing-time dependency has been established for over 300 medications of all classes. Chronotherapy schedules are shown to generate up to fivefold better drug tolerability and a doubling in drug efficacy as compared with conventional non-time-stipulated treatment schedules. The underlying mechanisms for the time-varying effects are rather complex. Circadian rhythms in pharmacokinetics, drug targets, disease severity, and tissue sensitivity are all possible contributing factors. Circadian rhythms in mammals are driven and sustained by a cellautonomous circadian clock system consisting of autoregulatory feedback loops (details are described in Chap. 1). The time of administration is a possible factor accounting for variations in the kinetics of a drug. Dependence of pharmacokinetics on dosing time has been described for over 50 drugs in humans. Time-dependent pharmacokinetics (also known as circadian pharmacokinetics or chronopharmacokinetics) aims to clarify the effects of the dosing time of the day on the pharmacokinetics. Circadian pharmacokinetics is associated with variations in drug exposure and therefore in pharmacological effects. Understanding of the mechanisms for circadian pharmacokinetics assumes great importance in advancing chronotherapeutics that aims to improve drug efficacy and to reduce side effects via dosing time optimization. This book focuses on the associations of the circadian clock with drug-metabolizing enzymes v

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Preface

and transporters and the molecular mechanisms for circadian regulation of these drug-processing proteins. It also covers the translation of circadian pharmacokinetics to drug chronotoxicity and chronoefficacy, which has significant implications for chronotherapeutics. Additionally, the non-pharmacokinetic factors (such as the rhythms in drug targets and in disease severity or flares of symptoms) contributing to chronotherapeutics are described. Guangzhou, China Guangzhou, China Guangzhou, China

Baojian Wu Danyi Lu Dong Dong

Contents

1

Introduction to Mammalian Circadian Clock System . . . . . . . . . . . Mengjing Zhao, Danyi Lu, Min Chen, and Baojian Wu

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Introduction to Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . Mengjing Zhao, Yi Wang, Min Chen, and Baojian Wu

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Circadian Clock and Metabolic Diseases . . . . . . . . . . . . . . . . . . . . . Shuai Wang, Feng Li, Ziyue Zhou, Zemin Yang, Jingpan Lin, and Dong Dong

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Circadian Clock and CYP Metabolism . . . . . . . . . . . . . . . . . . . . . . Tianpeng Zhang, Fangjun Yu, Lianxia Guo, and Dong Dong

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Circadian Clock and Non-CYP Phase I Metabolism . . . . . . . . . . . . Min Chen, Tianpeng Zhang, Danyi Lu, and Baojian Wu

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Circadian Clock and Phase II Metabolism . . . . . . . . . . . . . . . . . . . 113 Lianxia Guo, Dong Dong, Tianpeng Zhang, and Baojian Wu

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Circadian Clock and Uptake Transporters . . . . . . . . . . . . . . . . . . . 131 Danyi Lu, Menglin Chen, Yi Wang, Min Chen, and Baojian Wu

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Circadian Clock and Efflux Transporters . . . . . . . . . . . . . . . . . . . . 159 Danyi Lu, Huan Zhao, and Baojian Wu

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Role of Pharmacokinetics in Chronotherapeutics . . . . . . . . . . . . . . 187 Danyi Lu, Yi Wang, Menglin Chen, Huan Zhao, and Dong Dong

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Role of Non-Pharmacokinetic Factors in Chronoefficacy . . . . . . . . . 239 Shuai Wang, Yanke Lin, Lu Gao, Zemin Yang, and Dong Dong

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Chapter 1

Introduction to Mammalian Circadian Clock System Mengjing Zhao, Danyi Lu, Min Chen, and Baojian Wu

Abstract Organisms on Earth are dictated by circadian changes (e.g., sunlight, humidity, and temperature) in the environment caused by the planet’s rotation around its own axis. All forms of life have evolved biological clocks to adapt (and to synchronize) their physiology and behaviors to circadian environmental changes. This adaptation results in circadian rhythms (with a period of ~24 h) in many physiological and behavioral processes such as the sleep–wake cycle, body temperature, energy metabolism, cognitive performance, and hormonal release. Perturbation of circadian rhythms is associated with various pathologic conditions, including cancers, metabolic syndromes, cardiovascular diseases, sleep disorder, and depression. On the other hand, many diseases present circadian rhythms in flares of symptoms. Thus, it is of great interest to investigate circadian rhythms in depth, which would help to find means to combat diseases and to optimize drug treatment. In this chapter, we introduce mammalian circadian clock system and discuss the role of circadian clock in human health. Keywords Biological clock · Circadian clock · Physiological processes · Disease

1.1

Introduction

Organisms on Earth are dictated by daily changes in the environment such as changes in sunlight, humidity, and temperature. To adapt these external changes, organisms have developed circadian rhythms (or diurnal or daily or ~24 h rhythms) in most facets of physiology and behaviors. Circadian is a term derived from the Latin phrase “circa diem,” which means “about a day.” Circadian rhythms are regulated and maintained by the circadian clock system generally consisting of the input pathways that provide time cues (e.g., light, food, and temperature), the central M. Zhao · D. Lu · M. Chen · B. Wu (*) Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_1

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Fig. 1.1 Components of circadian clock system. Circadian clock system consists of the input pathways that provide time cues (e.g., light, food, and temperature), the central oscillator (pacemaker), and the output (or effector) pathways that control the behaviors, physiology, and metabolism of the organisms

oscillator (pacemaker), and the output (or effector) pathways that control the behaviors, physiology, and metabolism of the organisms (Fig. 1.1) [1, 2]. In mammals, the central pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Light as the main input signal is perceived by the intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina and transmitted to SCN via the retinohypothalamic tract (RHT). Clock genes are also present in the cells of various tissues/organs (such as the liver, heart, lung, kidney, and skin) in addition to SCN (Fig. 1.1). Thus, the peripheral tissues have their own clock systems. Since SCN as the central pacemaker coordinates circadian rhythms in other tissues/organs, the clock in SCN is called “central clock” or “maser clock” and clocks present in peripheral tissues are called “peripheral clocks” or “slave clocks.” The central clock and peripheral clocks constitute the hierarchical clock system (Fig. 1.1). The central clock synchronizes the peripheral clocks mainly via the nervous and hormonal pathways. Peripheral clocks can be entrained by glucocorticoid in a SCN-dependent manner. Peripheral clocks can be also entrained independent of SCN by external stimuli such as the feeding–fasting cycle. In turn, feedbacks (e.g., metabolic signals) from periphery may have various effects on the central clock [3]. Proper function of circadian clock is essential to human health. Disruption of circadian clock (e.g., due to genetic mutations, jet lag, or shift work) is associated with an increased risk for various types of diseases such as sleep disorders, depression, metabolic syndromes, cancers, inflammatory and cardiovascular diseases [4– 6]. Chronomedicine is a new rising discipline which combines modern medicine with chronobiology to explore the interactions between biological rhythms, diseases, and drugs. It is envisioned that chronomedicine will bring about new means to combat diseases and new approaches to optimize drug treatment [7]. In this chapter,

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we provide a detailed introduction to mammalian circadian clock system. Moreover, tight associations of circadian clock with health and diseases are discussed.

1.2

Circadian Rhythms

Biological rhythms are a universal feature of all organisms, that repeat or cycle with a period ranging from milliseconds to years. Circadian rhythms are the most prominent biological rhythms with a period of approximately 24 h (in the range of 20–28 h). Rhythms with periods of 28 h are termed “infradian rhythms.” Examples of biological events with ultradian rhythms are muscular twitches and respiration with periods of a few seconds, and non-rapid-eye movement (NREM) sleep/rapid-eye movement (REM) sleep alternating with an 80–120 min period [8, 9]. Infradian rhythms can be further classified to circaseptan (about 7 days), circatrigintan (about a month), and circannual (about a year) rhythms. Oestrous cycle, menstrual cycle, and seasonal variations in the reproductive system are infradian rhythms [10, 11]. Of all biological rhythms, circadian rhythms are best characterized so far. Key properties of circadian rhythms include (1) self-sustained and cell-autonomous (rhythms persist under the free-running or constant conditions), (2) temperature compensation (robustness of rhythms can be maintained over a broad range of physiological temperatures), and (3) can be entrained or reset by environmental factors (e.g., light, sporting, and food). When organisms are under entrainment of the light–dark cycle, the external time can be defined as “zeitgeber time” (ZT). The time of the beginning of day or lights on is defined as ZT0, and the time of the beginning of night or lights off is defined as ZT12. When organisms are under constant conditions such as constant darkness, “circadian time” (CT) is used to describe the endogenous time. CT0 corresponds to the onset of activity in diurnal animals, whereas CT12 represents onset of activity in nocturnal species.

1.3

Molecular Basis of Mammalian Circadian Clock

At the molecular level, circadian clock comprises a set of transcriptional activators and repressors that form three interlocked autoregulatory feedback loops (i.e., one core feedback loop and two auxiliary feedback loops) and generate circadian oscillations in gene expression (Fig. 1.2). In the main loop (loop 1), BMAL1 (brain and muscle Arnt-like protein) heterodimerizes with CLOCK (circadian locomotor output cycles kaput) or NPAS2 (neuronal PAS domain protein) and induces the transcription of three period (PER1, 2, 3) and two cryptochrome (CRY1, 2) genes as well as other clock-controlled genes (CCGs) through actions on E-box elements. PER and CRY proteins accumulate in the cytosol, enter the nucleus, and then inhibit the activity of CLOCK-BMAL1 or NPAS2-BMAL1 complex, thereby

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Fig. 1.2 Autoregulatory feedback loops of circadian clock system

downregulating their own expression and the expression of other CCGs. Once PER and CRY proteins are degraded, their inhibitory effects cease to exist and a new cycle of transcription and translation can be restarted. Degradation of PER and CRY proteins are controlled by casein kinases (CK1ε and CK1δ) and adenosine monophosphate kinase (AMPK), respectively. These kinases tag the proteins via phosphorylation for ubiquitination and proteasome degradation. In addition, ubiquitination of CRY proteins can be mediated by FBXL3. The core feedback loop is modulated by a second (auxiliary) loop (loop 2), in which two types of nuclear receptors, REV-ERBs (including REV-ERBα, β) and RORs (retinoic acid receptor-related orphan receptors, including RORα, β, γ) drive a circadian rhythm in BMAL1 transcription. RORs activate, whereas REV-ERBs repress, BMAL1 transcription by binding to the specific DNA element RORE (ROR response element). The REV-ERBs and RORs are also target genes of BMAL1/CLOCK. The third (auxiliary) loop (loop 3) involves DBP (albumin D site-binding protein) and E4BP4 (E4-binding protein 4). DBP activates, whereas E4BP4 represses, transcription of target genes through binding to the same ciselement D-box. These two factors play an antagonist role in regulating the expression of circadian genes including PERs and contribute to stability and robustness of the core feedback loop [12]. Additionally, epigenetic mechanisms (e.g., acetylation, deacetylation, and miRNAs) play a role in regulating expression and functions of clock genes [13, 14].

1 Introduction to Mammalian Circadian Clock System

1.4

5

Clock Genes

Clock genes are the genes whose protein products are required for generation and maintenance of the circadian rhythms. Mutations of clock genes result in disrupted circadian rhythms to a varying degree and in phenotypic abnormalities. In mammals, the major clock genes include CLOCK, BMAL1, NPAS2, PERs, CRYs, RORs, REVERBs, DBP, and E4BP4.

1.4.1

CLOCK, BMAL1, and NPAS2

CLOCK, BMAL1, and NPAS2 are bHLH/PAS (basic helix-loop-helix/PER-ARNTSIM) transcription factors which play a prominent role in the generation and maintenance of circadian rhythms in mammals [15–17]. CLOCK (or NPAS2) heterodimerizes with BMAL1 and activates the transcription of CCGs via binding to canonical E-box elements (CACGTG), non-canonical E-box elements (CANNTG), or E-box like sequences (e.g., CACGTT of mPer2) [18–20] (Fig. 1.3). The Clock gene is the first gene cloned in mammals with a circadian function. It was identified through a mutagenesis screen of circadian locomotor activity in mice. CLOCK is widely expressed in various tissues and organs (e.g., brain, lung, heart, liver, kidney, and intestine). The coding sequence of human CLOCK extends for 2538 bp and is 89% identical to its mouse ortholog; its deduced amino acid sequence is 846 residues long and is 96% identical to mouse CLOCK [21]. CLOCK has a histone acetyl transferase (HAT) like domain, which can acetylate Lys537 of its heterodimerization partner BMAL1 in a diurnally rhythmic manner [22, 23]. Lys537 acetylation of BMAL1 enhances the recruitment of CRY1 to the C-terminal region of BMAL1, leading to transcriptional repression. On the other hand, CRY1 binds to the PAS-B domain of CLOCK [24], preventing formation of heterodimer between CLOCK and BMAL1. These may be the mechanisms for inhibition of CLOCK/ BMAL1-mediated transcription by CRY. Clock-mutant mice maintained in constant darkness display circadian activity with a longer period of 27–28 h. These mice lack the ability to maintain rhythmicity after about 2 weeks in constant darkness. Furthermore, Clock-mutant mice develop Fig. 1.3 CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers activate the transcription of clockcontrolled genes via binding to E-box elements

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metabolic syndromes characterized by hyperglycemia, dyslipidemia, and hepatic steatosis [25]. In addition, genetic variations in CLOCK gene alter metabolic profiles in humans. CLOCK polymorphisms (rs4864548, rs3736544, rs1801260, rs11932595, and rs6843722) are associated with an increased susceptibility to metabolic diseases, including obesity, nonalcoholic fatty liver disease, and metabolic syndrome [26, 27]. CLOCK rs1801260 SNP (single nucleotide polymorphism) in CLOCK leads to a high plasma ghrelin concentration, short sleep duration, and altered eating behaviors, and ultimately to metabolic syndromes [28]. As noted above, BMAL1 generally heterodimerizes with CLOCK to activate the transcription of target genes. However, under certain circumstances, BMAL1 can regulate expression of genes (e.g., p21WAF1/CIP1 and Dio2) independent of CLOCK [29, 30]. Loss of Bmal1 gene in mice leads to behavioral arrhythmicity, disrupted rhythms in glucose and triglyceride levels, and eventually to metabolic diseases such as diabetes and obesity [31–33]. NPAS2 is suggested to be a functional homolog of CLOCK. Similar to CLOCK, NPAS2 forms a heterodimer with BMAL1 and transactivates genes through binding to an E-box element. NPAS2 and CLOCK play an overlapping role in regulating circadian rhythms; however, this overlapping role may be restricted to certain tissues such as SCN [34–36]. In the SCN, CLOCK and NPAS2 synergistically drive circadian gene expression, and the function of CLOCK can be compensated by NPAS2. However, in peripheral clocks (e.g., liver and lung clocks), no compensatory effects are observed for NPAS2 and CLOCK [37].

1.4.2

PERs and CRYs

PER1, 2, and 3 are components of the negative limb of circadian clock in mammals. PER1, 2, and 3 are called PAS proteins as they possess PAS (Per-Arnt-Sim) domain that has a role in protein–protein interactions [38, 39]. Additionally, PER2 contains an LXXLL motif which is involved in binding of PER2 to REV-ERBα and PPARα [40]. PER1 and 2 are essential regulators of the clock system in the SCN, whereas the role of PER3 is subtle [41]. PER3 appears to play a role in peripheral clock system and physiology as genetic loss or variation of PER3 leads to abnormal metabolic phenotypes in humans and mice [42–44]. CRY1 and 2 are also components of the negative limb of mammalian circadian clock. Compared with wild-type mice, Cry1-knockout mice display a rhythm with a 1 h shorter period, Cry2-knockout mice display a rhythm with a 1 h longer period, while Cry1 and Cry2 double knockout mice are totally arrhythmic [45, 46]. As noted previously, PERs and CRYs function to inhibit CLOCK/BMAL1 mediated transactivation that is essential for the molecular clock to operate properly. In addition to transcriptional activation by CLOCK/BMAL1, the levels of PERs and CRYs are controlled by phosphorylation and degradation (Fig. 1.4). Casein kinase (CK) 1ε and CK1δ phosphorylate the PER proteins. The phosphorylated PERs are subsequently ubiquitinated by β-TrCP (β-transducin repeat-containing protein) and

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Fig. 1.4 Control of PER and CRY levels by BMAL1/CLOCK, phosphorylation, and degradation

degraded by the 26S proteasome [47, 48]. AMPK phosphorylates CRY proteins [49]. The phosphorylated CRYs are ubiquitinated by FBXL3, and then subjected to proteasomal degradation [50]. Notably, FBXL21 forms an SCF E3 ligase complex and protects CRYs from FBXL3-mediated degradation [51] (Fig. 1.4).

1.4.3

REV-ERBs and RORs

REV-ERBα [also known as NR1D1 (nuclear receptor subfamily 1 group D member 1)] is a nuclear receptor and a core component of the circadian clock system. REV-ERBα was discovered in 1989 and its name was derived from genomic location on the reverse DNA strand of v-erbA oncogene (also called “thyroid hormone receptor α”) found in the avian erythroblastosis virus [52, 53]. About 5 years later, REV-ERBβ (NR1D2), the other member of NR1D subfamily, was identified [54]. Due to the lack of an activation function 2 (AF2, a motif for recognition of co-activators) in ligand binding domain, REV-ERBα/β cannot activate gene transcription [55]. Instead, REV-ERBα/β function as transcriptional repressors, and inhibit gene transcription by recruiting co-repressors nuclear receptor co-repressor 1 (NCOR1) and histone deacetylase 3 (HDAC3) [56]. REV-ERBα generally functions as a monomer and binds to a consensus half-site motif (A/G) GGTCA preceded by an A/T rich 50 sequence (named RORE or RevRE) on target gene promoters (Fig. 1.5a) [57]. In some cases, REV-ERBα can bind to direct repeats of RORE separated by 2 bp (RevDR2) as a dimer (Fig. 1.5b). Moreover, two REV-ERBα molecules can separately bind to two adjacent ROREs

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Fig. 1.5 General modes for regulation of target gene transcription by REV-ERBα

and recruit co-repressors (i.e., NCOR1 and HDAC3) to regulate gene transcription (Fig. 1.5c). In addition to direct regulation, REV-ERBα indirectly regulates gene transcription by interacting with other transcription factors (e.g., E4BP4, HNF6, GR, and NF-Y) (Fig. 1.5d) [58–62]. REV-ERBα may play a more important role in regulating circadian rhythms as compared to REV-ERBβ. Rev-erbα-deficient mice show disrupted circadian rhythms with a shortened period, whereas Rev-erbβ ablation has negligible effects on circadian rhythms [63]. Recent years of studies uncover a broad role of REV-ERBα in pathological conditions, including sleep disorders, depression, inflammatory and metabolic diseases [64, 65]. Accordingly, REV-ERBα ligands have been shown to ameliorate these pathological conditions [66]. Therefore, REV-ERBα is regarded as a promising drug target. RORs (including RORα, β, γ) are nuclear receptors that belong to the steroid hormone receptor family [67, 68]. The three ROR homologs have distinct patterns of tissue distribution. RORα is expressed in various tissues including the brain, heart, liver, testis, and skin [69]. RORβ is abundantly expressed in the brain [70]. RORγ is highly expressed in the thymus [71]. RORs and REV-ERBs bind to the same response element RORE. RORs activate, whereas REV-ERBs repress, gene transcription. RORs and REV-ERBs are target genes of BMAL1. In turn, they can regulate Bmal1 transcription and expression. REV-ERBs are required for rhythmic Bmal1 expression [72]. In contrast, the RORs contribute to Bmal1 amplitude but are dispensable for Bmal1 rhythm [72]. In addition to regulating circadian rhythm, RORs play a critical role in various physiological processes such as cell differentiation and immune responses [73].

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PAR bZip Proteins (DBP, HLF, and TEF) and E4BP4

The PAR-domain basic leucine zipper (PAR bZip) transcription factors contain three members, namely DBP, TEF (thyrotroph embryonic factor), and HLF (hepatic leukemia factor) [74]. They activate the transcription of target genes (e.g., PER1) via binding to D-box elements (Fig. 1.6). PAR bZip factors are directly regulated by CLOCK/BMAL1 through E-box elements, a main mechanism for generating circadian oscillations in their expression [75] (Fig. 1.6). PAR bZip proteins have been shown to regulate the expression of enzymes (e.g., Cyp2a4, Cyp2a5, Cyp2c6, and Ces3) and transporters (e.g., P-gp and Mrp2) involved in drug metabolism and detoxification [76–78]. E4BP4 is a basic leucine zipper (bZIP) protein which usually functions as a transcriptional repressor [79]. The characteristic feature that allows E4BP4 to exert transcriptional repression activity is a repression domain lying between residues 299 and 363 that interacts with the TBP binding repressor protein Dr1 [80]. However, E4BP4 repressor activity may be attained through Dr1-independent mechanisms. E4BP4 (in the form of GALδBstB) is still capable of repressing a GAL-MLP chimeric promoter in reactions apparently lacking Dr1. Notably, in mammalian T lymphocytes, E4BP4 binds to the promoter of the IL3 gene and acts as a transcriptional activator, instead of a repressor [81]. This difference in the type of action may depend on cell-type factors such as the presence or absence of co-activators or co-repressors [82]. E4BP4 has been implicated in various physiological processes including cell differentiation, apoptosis, inflammatory responses, and xenobiotic metabolism [83]. E4BP4 is directly controlled by the RORE-binding protein RORs and REV-ERBs, a main source of circadian oscillations in its expression (Fig. 1.6). The rhythmic pattern of E4BP4 is anti-phase to the PAR bZip proteins (DBP, HLF, and TEF) in the SCN and liver (Fig. 1.6). E4BP4 competes for the same sequence D-box to antagonize the transactivation effects of PAR bZip proteins

Fig. 1.6 Circadian regulators and target genes of PAR bZip proteins and E4BP4

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(Fig. 1.6). Ohno et al. reveal protein–protein interactions between E4BP4 and PER2, which may regulate repressor activity of PER and impact the core circadian clock network [84].

1.5

Circadian Clock and Human Health

Disruption of circadian rhythms (e.g., caused by shift work, jet lag, or sleep loss) contributes to the development of obesity and metabolic diseases such as diabetes and hypertension in humans [85–88]. Inappropriate timing of food intake and fasting/feeding cycle result in disturbances of the temporal coordination of metabolism with physiology, thereby promoting metabolic diseases [88, 89]. Genetic variations in circadian clock genes lead to increased risks for obesity and metabolic disorders. Of note, CLOCK polymorphism (rs3736544) is associated with predisposition to obesity [90]. Two single nucleotide polymorphisms rs7947951 and rs9633835 in BMAL1 are respectively associated with type 2 diabetes and hypertension [91]. Consistently, ablation of Bmal1, Clock, Per2, Cry1/Cry2, or Rev-erbα in mice result in increased susceptibility to obesity and metabolic disorders [92– 94]. For example, Bmal1 deficient mice exhibit altered glucose metabolism and impaired insulin signaling, leading to insulin resistance and obesity [95]. Clockmutant mice are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia [96]. In general, circadian clock controls metabolic homeostasis by regulating the circadian expression and activity of enzymes (e.g., SIRT1, AMPK, NAD+, heme, CYP7A1, ALAS1, HMGCR, NAMPT, and PPARα/γ) and hormones (including insulin, glucagon, adiponectin, corticosterone, leptin, and ghrelin) [97– 99]. Circadian homeostasis of these enzymes and hormones is essential to health as loss of rhythms leads to metabolic abnormalities. For instance, loss of circadian rhythmicity in insulin secretion (i.e., glucose metabolism) contributes to the development of metabolic disorders such as type 2 diabetes [100]. Deletion of Pparγ in mice leads to loss of diurnal variations in food intake and other metabolic parameters such as blood pressure, heart rate, and heat production [101]. The role of circadian clock in regulation of cardiovascular system can be exemplified by circadian rhythms in cardiovascular parameters and cardiovascular events. A broad range of cardiovascular parameters display significant circadian rhythms in humans [102, 103] (Table 1.1). Disruption of circadian rhythms has been associated with cardiovascular diseases including hypertension, myocardial infarction, ischemic stroke, and premature death [104, 105]. Cardiovascular events such as myocardial infarction and stroke vary according to times of the day, with higher frequencies in the morning and lower frequencies in the sleeping hours (Table 1.1). Animal studies have revealed that various clock genes (e.g., Clock, Bmal1, Per2, Dbp, Hlf, and Tef) are involved in regulating cardiovascular circadian rhythms and cardiac diseases. Cardiomyocyte-specific Clock-mutant mice show a significant reduction in heart rate as compared to wild-type mice [106]. The rhythms in heart rate and blood

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Table 1.1 Circadian rhythm of cardiovascular parameters/events in humans Parameters/ events Heart rate Blood pressure Sympathetic activity Parasympathetic activity Platelet aggregability Ventricular arrhythmias Sudden cardiac death Myocardial infarction Stroke Transient ischemia

Peak Between 10:00 AM and 12:00 AM Between 10:00 AM and 12 AM Daytime

Trough Between 3:00 AM and 5:00 AM

Refs [110]

Between 3:00 AM and 6:00 AM

[111, 112]

Nighttime

[113]

Nighttime

Daytime

[113]

In the morning

Remain at a lower level throughout the rest of the 24 hours In the sleeping hours

[114] [115]

In the sleeping hours

[116]

Between 11:00 PM and midnight

[117]

From midnight to 6:00 AM

[118]

In the sleeping hours

[119]

In the morning Between 9:00 AM and 11:00 AM Between 9:00 AM and 11:00 AM Between 6:00 AM and 12:00 AM Between 6:00 AM and 12:00 AM

Table 1.2 Circadian rhythms in flares of symptoms for immune diseases Parameters Rheumatoid arthritis Asthma

Symptoms Joint stiffness and pain

Allergic rhinitis

Sneezing, nasal congestion, and nasal rhinorrhea

Dyspnea and cough

Peaking time In the early morning In the early morning In the early morning

Refs [124] [125, 126] [127]

pressure are lost in Bmal1-knockout mice [107]. Per2 ablation leads to endothelia dysfunction [108]. Knockout of Dbp, Hlf, or Tef induces cardiomyopathy, cardiac hypertrophy, and left ventricular dysfunction [109]. Circadian clock has emerged as an important regulator of immune functions. Key parameters of the immune system (e.g., the number of circulating immune cells and the levels of pro- and anti-inflammatory hormones and cytokines) exhibit robust circadian rhythms [120, 121]. Alterations in circadian rhythms (e.g., caused by shift work and chronic jet lag) lead to disturbed immune responses [122]. In addition, the severity of immune diseases (flares of symptoms) such as rheumatoid arthritis, asthma, and allergic rhinitis vary greatly according to time-of-day (Table 1.2). Clock components (e.g., BMAL1, CLOCK, PERs, CRYs, REV-ERBs, and RORs) have been implicated in the regulation of immune system [123] (Fig. 1.7). BMAL1, in a heterodimer with CLOCK, regulates the expression of Ccl2, Ccl8, and Nrf2.

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Fig. 1.7 Regulation of the immune system by clock genes. BMAL1, in a heterodimer with CLOCK, regulates the expression of Ccl2, Ccl8, and Nrf2. BMAL1 is also able to dimerize with RelB, thus blocking a subunit of the proinflammatory transcription factor NF-κB. CLOCK acetylates the RelA subunit (NF-κB) and glucocorticoid receptors, thereby regulating their DNA binding capacity. PER binds together with PPARγ to an E-box in the Ccr2 promoter region, downregulating its transcription. CRY dimerizes with the adenylyl cyclase (AC) to inhibit its function. RORα upregulates the transcription of IκBα, the major transcriptional inhibitor of the NFκB signaling pathway, and Ccl2. REV-ERBα inhibits the transcription of Ccl2, Il6, Il1b, and Nlrp3

BMAL1 is also able to dimerize with RelB, thus blocking a subunit of the proinflammatory transcription factor NF-κB. CLOCK acetylates the RelA subunit (NF-κB) and glucocorticoid receptors, thereby regulating their DNA binding capacity. PER binds together with PPARγ to an E-box in the Ccr2 promoter region, downregulating its transcription. CRY dimerizes with the adenylyl cyclase (AC) to inhibit its function. RORα upregulates the transcription of IκBα, the major transcriptional inhibitor of the NFκB signaling pathway and Ccl2. REV-ERBα inhibits the transcription of Ccl2, Il6, Il1b, and Nlrp3. Circadian clock plays a vital role in aging and longevity. Prolonged disruptions to the clock and genetic deficiency of clock genes are associated with accelerated aging. Bmal1-deficient mice have reduced lifespans (37 weeks versus 30 months for normal mice) and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, and organ shrinkage [128]. Clockmutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice [129]. On the other hand, the aging process leads to changes and disruption in circadian rhythms, exemplified by changes in the sleep quality, quantity, and architecture [130]. This is essentially due to decreased sensitivity to light

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(entrainment), jeopardized melatonin production (pineal calcification), and compromised SCN functions [131–133]. Circadian rhythm disruptions (e.g., via jet lag, shift work, sleep disruption, and exposure to light at night) are associated with increased cancer risk, including prostate, breast, colon, liver, pancreas, ovary, and lung cancers [134–137]. Epidemiological studies have found relationships between daily eating patterns and cancer risk. Women who eat all their calories within a period of 11 h, leaving 13 h of overnight fast, have a significantly lower risk of breast cancer [138]. Eating dinner before 9:00 PM correlates with significantly reduced risks of prostate and breast cancers [139]. On the other hand, enforcement of biological rhythms may impair cancer progression and recurrence, and increase the quality of life. Patients with metastatic colorectal cancer who have a robust rest/activity rhythm have better survival and quality of life than patients with erratic periods of rest/activity and poor sleep [140, 141]. The important role of circadian rhythms in cancers can be replicated in animal models. Chronic jet lag or SCN ablation in normal mice dramatically accelerates tumor initiation and progression [142]. Also, genetic disruption of clock genes (e.g., Clock, Bmal1, Pers, and Crys) increases tumor formation [143, 144]. Circadian clock impacts cancer development and progression through regulation of multiple hallmarks of cancer, including cell cycle, apoptosis, and DNA repair. Each phase of the cell cycle has the potential to be influenced by the circadian clock. For example, PER1 and the circadian gene Timeless (TIM) inhibit the G1-S transition through interaction with ataxia-telangiectasia-mutated (ATM) and checkpoint 2 (CHK2), causing cell cycle arrest (Fig. 1.8) [145]. CRY1 promotes cell cycle progression by inhibiting WEE1, the G2-M regulatory kinase, and thereby inducing mitotic entry (Fig. 1.8) [146]. Conversely, CRY1 restricts mitosis by modulating the ATM, ATR (ATM and Rad3-related), CHK1-mediated G2-M transition by interacting with TIM in a circadian-controlled manner (Fig. 1.8) [147, 148]. Circadian factors may promote or restrict apoptosis, depending on cellular context and clock status. For instance, PER2 sensitizes cancer cells to radiation-induced apoptosis through activation of Myc-mediated proapoptotic pathways (Fig. 1.8) [149]. PER1 inhibits apoptosis through upregulation of anti-apoptotic BCL-2 and downregulation of proapoptotic BAX (Fig. 1.8) [150]. BMAL1/CLOCK inhibits apoptosis via regulation of the anti-apoptotic regulator DEC2 (Fig. 1.8) [151]. Clock genes play an important role in DNA damage responses. Cry2/ mice exhibits dampened circadian rhythm in the nucleotide excision repair gene XPA (Fig. 1.8) [152, 153]. CRY2 interacts with ATR and CHK1 to regulate intra-S checkpoint function [154] (Fig. 1.8). PER1 directly interacts with ATM/CHK2 to promote DNA repair and genomic stability in response to radiation-induced double-strand breaks [145] (Fig. 1.8).

Fig. 1.8 Circadian regulation of cell cycle, apoptosis, and DNA repair. PER1 and the circadian gene Timeless (TIM) inhibit the G1-S transition through interaction with ataxia-telangiectasia-mutated (ATM) and checkpoint 2 (CHK2), causing cell cycle arrest. CRY1 promotes cell cycle progression by inhibiting WEE1, the G2-M regulatory kinase, and thereby inducing mitotic entry. Conversely, CRY1 restricts mitosis by modulating the ATM, ATR, CHK1-mediated G2-M transition by interacting with TIM in a circadian-controlled manner. Circadian factors may promote or restrict apoptosis, depending on cellular context and clock status. For instance, PER2 sensitizes cancer cells to radiation-induced apoptosis through activation of Myc-mediated proapoptotic pathways. PER1 inhibits apoptosis through upregulation of anti-apoptotic BCL-2 and downregulation of proapoptotic BAX. BMAL1/CLOCK inhibits apoptosis via regulation of the anti-apoptotic regulator DEC2. Clock genes play an important role in DNA damage responses. Cry2-/- mice exhibits dampened circadian rhythm in the nucleotide excision repair gene XPA. CRY2 interacts with ATR (ATM and Rad3-related) and CHK1 to regulate intra-S checkpoint function. PER1 directly interacts with ATM/CHK2 to promote DNA repair and genomic stability in response to radiation-induced double-strand breaks (DSBs)

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97. Eckel-Mahan K, Sassone-Corsi P (2009) Metabolism control by the circadian clock and vice versa. Nat Struct Mol Biol 16(5):462–467 98. Oren F (2012) Circadian rhythms and obesity in mammals. ISRN Obes 18(2012):437198 99. Kalsbeek A, Yi CX et al (2010) The hypothalamic clock and its control of glucose homeostasis. Trends Endocrinol Metab 21(7):402–410 100. Boden G, Chen G et al (1999) Disruption of circadian insulin secretion is associated with reduced glucose uptake in first-degree relatives of patients with type 2 diabetes. Diabetes 48 (11):2182–2188 101. Yang G, Jia Z et al (2012) Systemic PPARγ deletion impairs circadian rhythms of behavior and metabolism. PLoS One 7:e38117 102. Kollias GE et al (2009) Diurnal variation of endothelial function and arterial stiffness in hypertension. J Hum Hypertens 23:597 103. Degaute JP, van de Borne P et al (1991) Quantitative analysis of the 24-hour blood pressure and heart rate patterns in young men. Hypertension 18(2):199–210 104. Vyas MV, Garg AX et al (2012) Shift work and vascular events: systematic review and metaanalysis. BMJ 345:e4800 105. Lo SH, Lin LY et al (2010) Working the night shift causes increased vascular stress and delayed recovery in young women. Chronobiol Int 27(7):1454–1468 106. Bray MS, Shaw CA et al (2008) Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression. Am J Physiol Heart Circ Physiol 294(2):H1036–H1047 107. Curtis AM, Cheng Y et al (2007) Circadian variation of blood pressure and the vascular response to asynchronous stress. Proc Natl Acad Sci U S A 104(9):3450–3455 108. Viswambharan H, Carvas JM et al (2007) Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation 115(16):2188–2195 109. Wang Q, Maillard M et al (2010) Cardiac hypertrophy, low blood pressure, and low aldosterone levels in mice devoid of the three circadian PAR bZip transcription factors DBP, HLF, and TEF. Am J Physiol Regul Integr Comp Physiol 299(4):R1013–R1019 110. De Scalzi M, De Leonardis V et al (1984) Heart rate and premature beats: a chronobiologic study. Giornale Italiano di Cardiologia 14:465–470 111. Harshfield GA, Barbeau P et al (2000) Racial differences in the influence of body size on ambulatory blood pressure in youths. Blood Press Monit 5:59–63 112. Kario K, Matsuo T et al (1996) Relation between nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensives: advanced silent cerebrovascular damage in extreme-dippers. Hypertension 27:130–135 113. Furlan R, Guzzetti S et al (1990) Continuous 24-hour assessment of the neural regulation of systemic arterial pressure and RR variabilities in ambulant subjects. Circulation 81 (2):537–547 114. Andrews NP, Gralnick HR et al (1996) Mechanisms underlying the morning increase in platelet aggregation: a flow cytometry study. J Am Coll Cardiol 28:1789–1795 115. Goldstein S, Zoble RG et al (1996) Relation of circadian ventricular ectopic activity to cardiac mortality. CAST Investigators. Am J Cardiol 78:881–885 116. Muller JE, Ludmer PL et al (1987) Circadian variation in the frequency of sudden cardiac death. Circulation 75:131–138 117. Willich SN, Linderer T et al (1989) Increased morning incidence of myocardial infarction in the ISAM study: absence with prior beta-adrenergic blockade. Circulation 80:853–858 118. Elliott WJ (1998) Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 29:992–996 119. Rocco MB, Barry J et al (1987) Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation 75:395–400 120. Haus E, Smolensky MH (1999) Biologic rhythms in the immune system. Chronobiol Int 16 (5):581–622

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147. Kang THH, Leem SHH (2014) Modulation of ATR-mediated DNA damage checkpoint response by cryptochrome 1. Nucleic Acids Res 42:4427–4434 148. Kondratov RV, Antoch MP (2007) Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends Cell Biol 17:311–317 149. Papagiannakopoulos T, Bauer MR et al (2016) Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab 24(2):324–331 150. Li HX, Yang K et al (2016) Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae 38(2):155–163 151. Liu Y, Sato F et al (2010) Anti-apoptotic effect of the basic helix-loop-helix (bHLH) transcription factor DEC2 in human breast cancer cells. Genes Cells 15:315–325 152. Kang T-HH, Reardon JT et al (2011) Regulation of nucleotide excision repair activity by transcriptional and post-transcriptional control of the XPA protein. Nucleic Acids Res 39:3176–3187 153. Kang T-HH, Lindsey-Boltz LA et al (2010) Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase. Proc Natl Acad Sci U S A 107:4890–4895 154. Barnes JW, Tischkau SA et al (2003) Requirement of mammalian timeless for circadian rhythmicity. Science 302:439–442

Chapter 2

Introduction to Pharmacokinetics Mengjing Zhao, Yi Wang, Min Chen, and Baojian Wu

Abstract Pharmacokinetics (drug kinetics) deals with the in vivo fate or disposition processes of the drug (i.e., how the body does to the drug) that determine drug exposure in the body and therefore pharmacological effects. In general, drug molecules undergo four main disposition processes in the body, namely absorption, distribution, metabolism, and excretion (ADME, the so-called four components of pharmacokinetics). Pharmacokinetic study is an integral part of drug research and development. Poor pharmacokinetic property (e.g., poor absorption, fast clearance, and toxic metabolite) is reported to be one of the main causes of drug attrition. Pharmacokinetic behaviors are influenced by various physiological factors such as blood flow, gastric motility, hepatic enzyme activity, and renal function. The time of administration is an additional variable influencing the pharmacokinetics (dosing time-dependent pharmacokinetics is defined as chronopharmacokinetics). In this chapter, we introduce the ADME processes and discuss the factors affecting the pharmacokinetics. Keywords Pharmacokinetics · ADME · Time-dependent pharmacokinetics

2.1

ADME Processes and Pharmacokinetics

Pharmacokinetics (drug kinetics) deals with the in vivo fate or disposition processes of the drug (i.e., how the body does to the drug) that determine drug exposure in the body and therefore pharmacological effects. In general, drug molecules undergo four main disposition processes in the body, namely absorption, distribution, metabolism, and excretion (ADME, the so-called four components of pharmacokinetics). Pharmacokinetic study is an integral part of drug research and development. ADME processes may vary according to the route of drug administration. For example, there M. Zhao · Y. Wang · M. Chen (*) · B. Wu Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_2

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Fig. 2.1 ADME processes of drugs following oral administration. In general, oral drugs are taken by mouth, swallowed with fluid, and absorbed via the gastrointestinal tract to the systemic circulation. Then, drugs are distributed to various tissues and organs including the liver and kidney. Drugs can be eliminated from the body either by metabolism (in the liver) or excretion of parent drug and/or metabolites (in the kidney). Additionally, drugs may be eliminated via biliary excretion

is absorption process for oral administration, but no absorption process for intravenous administration. Figure 2.1 shows the ADME processes of drugs following oral administration. In general, oral drugs are taken by mouth, swallowed with fluid, and absorbed via the gastrointestinal tract to the systemic circulation (Fig. 2.1). Then, drugs are distributed to various tissues and organs including the liver and kidney (Fig. 2.1). Drugs can be eliminated from the body either by metabolism (in the liver) or excretion of parent drug and/or metabolites (in the kidney) (Fig. 2.1). Additionally, drugs may be eliminated via biliary excretion (Fig. 2.1).

2.2

Drug Absorption

Absorption is the transportation of the drug from the site of administration to the systemic circulation. The routes of drug administration are generally divided into two categories: intravascular (e.g., intravenous) and extravascular (e.g., oral, topical, intramuscular) administration (Table 2.1) [1]. Except for intravascular administration, absorption process exists in all routes of administration. Many factors influence drug absorption, including physicochemical properties (e.g., molecular size, lipid solubility, and degree of ionization) of the drug, dosage forms (e.g., tablet and solution), blood flow (at the site of administration), and routes of administration.

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Table 2.1 Routes of drug administration Administration Oral Intravenous Mouth Inhalation Topical Intramuscular Subcutaneous

2.2.1

Site of absorption Gastrointestinal tract Not applicable Oral cavity or sublingual Lungs Skin Muscle Skin/muscle

First-pass metabolism Yes No No No No No No

Gastrointestinal Absorption

Oral is the most common route of drug administration as it possesses many advantages such as safety, good patient compliance, ease of ingestion, and pain avoidance [2]. However, oral administration has drawbacks. Drugs administered orally must pass through the intestine and liver before reaching the systemic circulation. Some drugs can be metabolized by enzymes in gastrointestinal tract and liver. Thus, the concentration of the drug is significantly reduced before it reaches the systemic circulation. This phenomenon is known as the first-pass effect, which results in reduced drug absorption and attenuated therapeutic effect. Physiologic parameters of the gastrointestinal tract, such as blood flow, pH, and gastric emptying, can affect the absorption of drugs. Gastrointestinal pH perhaps is one of the most important influencing factors. A weak acid tends to be preferentially absorbed in the acidic environment, whereas a weak base tends to be better absorbed in the alkaline environment. Large surface area and high blood flow make small intestine the primary site of absorption for most drugs. Over 99% of oral drugs are absorbed in the small intestine [3]. Intestinal epithelium forms a selective barrier against the entry of drugs into blood. A molecule can move across the intestinal epithelia via paracellular or transcellular routes [4] (Fig. 2.2). Transcellular (membrane) transport can be categorized to passive transport and active transport according to whether energy is required or not. Passive transport is the movement of substances across the membrane (using their concentration gradient) without energy expenditure. There are two types of passive transport: simple diffusion and facilitated diffusion. In contrast, active transport is the movement of substances across the membrane (usually against their concentration gradient) using energy from adenosine triphosphate (ATP) hydrolysis or downhill movement of another solute. Notably, facilitated diffusion and active transport (except endocytosis) belong to transporter-mediated membrane transport as membrane transporters are required for substance transport in these processes.

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Fig. 2.2 Major routes of drug movement across intestinal epithelia

2.2.2

Enterohepatic Recycling

The gastrointestinal tract has also evolved into an excretory organ for elimination of non-absorbed solid wastes and other metabolic by-products excreted in the bile [5]. The bile duct drains into the upper small intestine. This is linked to a phenomenon called enterohepatic recycling, whereby a drug from the systemic circulation is excreted into the bile and is reabsorbed from the small intestine into the blood stream. In many cases, drugs that are metabolized in the liver by phase II conjugation reactions are excreted into the bile and “unconjugated” by resident bacterial flora, which generates free drug for reabsorption. The feature of the enterohepatic recycling process is a “hump” (or “second peak”) in the plasma drug concentration-time profile after administration (Fig. 2.3).

2.2.3

Bioavailability

Bioavailability is the most useful pharmacokinetic parameter to characterize the extent of drug absorption. Bioavailability (F) is defined as the fraction (percentage) of administered drug that reaches the systemic circulation [6]. Intravenous and intraarterial injections transfer the drug directly into systemic blood circulation thus provide 100% bioavailability. Drugs administrated by extravascular routes

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Fig. 2.3 Representative concentration-time profile showing a second peak resulted from enterohepatic recycling

Fig. 2.4 Schematic diagram for AUC

usually have bioavailability less than 100%. The absolute bioavailability is calculated as the area under the curve (AUC, Fig. 2.4) following extravascular administration divided by the AUC after intravenous (i.v.) bolus, appropriately correcting for dose (Eq. 2.1). F¼

2.3

AUCe:v: Dosei:v: ∙ AUCi:v: Dosee:v:

ð2:1Þ

Drug Distribution

Distribution refers to movement of the drug from the systemic circulation to tissues. A sufficient concentration in the site of action is required to generate therapeutic effects. Distribution of drugs to peripheral tissues is dependent on four factors: (1) the physiochemical properties of the drug, (2) the concentration gradient established between the blood and tissue, (3) the ratio of blood flow to tissue mass, and (4) the affinity of the drug for tissue constituents [6].

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Volume of Distribution

Drug distribution can be measured either by the passage of drugs from the blood circulation or by actual tissue measurement. In general, most data are obtained by using the former method. The volume of distribution of a drug is a theoretical number that assumes the drug is at equal concentration in the tissue to that in the blood circulation and calculates what volume (or mass) of tissue is required to give that concentration. It can provide an indication on the type of distribution pattern. The volume of distribution is calculated from the amount of drug in the body (i.e., the dose) divided by the plasma concentration (Eq. 2.2). V d ¼ Dbody =Dplasma

ð2:2Þ

where Dbody is the amount of drug in the body at any time and Dplasma is the corresponding amount of drug in the blood at the same time. The reference volumes where drug distribution can take place are: (1) plasma volume (3 L in a standard 70 kg human, ~4% of body weight), (2) extracellular space (15 L, ~20% of body weight), and (3) total body water (42 L, ~60% of body weight) [7]. When the volume of distribution is equal or higher than the total body water, then the drug is distributed into tissues. A volume of distribution smaller than the total amount of body water indicates that the drug is retained in plasma or in the extracellular water and probably is bound to plasma proteins. Volume of distribution, therefore, partially reflects tissue affinity.

2.3.2

Tissue Barriers to Distribution

Some organs have unique anatomical barriers to drug penetration. The most famous example is the blood–brain barrier that has a glial cell layer interposed between the capillary endothelium and the nervous tissue. Only nonionized lipid-soluble compounds can penetrate this barrier. The barriers usually possess selective efflux transporters that remove chemicals from the vital tissues. P-glycoprotein (P-gp) is one of the best understood efflux transporters [8]. P-gp is expressed in the intestinal tract, brain, placenta, testis, and proximal renal tubules. It can limit drug penetration to the tissues such as intestine, brain, and placenta, among others.

2.3.3

Protein Binding

Binding to plasma and tissue proteins influence the distribution of a drug into the body. Albumin is the most common protein to which the drugs can bind [9]. Within the different compartments, drugs can exist in bound or unbound form. However,

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only the unbound drug can pass through the cellular barriers between compartments and can induce a pharmacological or a toxic effect. In general, drugs with an extensive plasma protein binding tend to have a lower volume of distribution as they stay mainly in the blood compartment. Plasma protein binding can be a source of intra-individual and inter-individual variability in the pharmacokinetics due to pathological status and genetic variability.

2.4

Drug Metabolism

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. Typical drug metabolism reactions include oxidation, reduction, hydrolysis, hydration, and conjugation [10]. Metabolism is generally a detoxification pathway as the metabolite is pharmacologically inactive. However, in some cases, metabolism can enhance drug effect because the metabolite is more active. Drug metabolism may elicit toxicity due to the formation of toxic metabolite. Drug metabolism mainly occurs in the liver, intestine, kidney, and lung. Of note, the liver contributes the most to overall drug metabolism because the drugmetabolizing enzymes are abundantly expressed in the liver.

2.4.1

Phase I and Phase II Reactions

Drug metabolism reactions can be divided into phase I and phase II reactions (Table 2.2). Phase I reactions include oxidation, reduction, hydrolysis, hydration, and isomerization. Phase II reactions include glucuronidation, sulfation, methylation, acetylation, and glutathione conjugation. Phase II metabolism generally increases drug solubility due to the addition of a polar group (e.g., glucuronic acid and glutathione), facilitating drug excretion from the body. Phase I metabolites can act as the substrates for phase II enzymes. According to the types of metabolic reactions, drug-metabolizing enzymes are divided into phase I enzymes and phase II enzymes [11]. Phase I enzymes mainly include cytochromes P450 (CYPs), flavincontaining monooxygenases (FMOs), carboxylesterases (CESs), aldehyde dehydrogenases (ALDHs), aldehyde oxidases (AOs), monoamine oxidases (MAOs), and alcohol dehydrogenases (ADHs). Phase II enzymes include Table 2.2 Phase I and phase II reactions

Phase I reactions Oxidation Reduction Hydrolysis Hydration Isomerization

Phase II reactions Glucuronidation Sulfation Methylation Acetylation Glutathione conjugation

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UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), and N-acetyltransferases (NATs) [12].

2.4.2

Hepatic Clearance

The ability of the liver to remove drugs from the blood, defined as hepatic clearance, is related to two variables: the intrinsic hepatic clearance and hepatic blood flow (Eq. 2.3):  CLH ¼ QH

 CLint ¼ QH ∙ E H QH þ CLint

ð2:3Þ

where CLH is the hepatic clearance (the subscript H denotes “hepatic”), QH is the hepatic blood flow, CLint is the intrinsic hepatic clearance, and CLint/(QH + CLint) is the hepatic extraction ratio or EH. The intrinsic clearance is conceptualized as the maximal ability of the liver to extract or metabolize drugs when hepatic blood flow is not limiting. As indicated in Eq. 2.3, when CLint >> QH (EH  1.0), CLH is only dependent on the QH. In this case, the more blood passing through the liver, the more drug molecules will be extracted by the liver for metabolic elimination. In contrast, if CLint 12 weeks of age in male and 22 weeks in females) Increased corticosterone/glucose intolerance

C57BL/6J

Decreased body weight

[23]

Mice

Decreased total triacylglycerol and nonesterified fatty acids Increased serum leptin and body weight

[24]

Nondipping hypertension Decreased fasting glucose and triglyceride/ increased free fatty acid Increased adiposity and mild hyperglycemia

[25] [26]

Sv129OlaHsd  BALB/ c SV129/OlaHsd

Increased serum triglyceride

[28]

Decreased bile acid/unchanged cholesterol

[29]

129/Sv  C57BL/6J

Decreased hepatic triglyceride and cholesterol/increased plasma LDL and HDL cholesterol Hyperhomocysteinemia

[30]

C57BL/6J C57BL/6J

C57BL/6J C57BL/6J C57BL/6J

C57BL/6J

[17]

[20] [21] [22] [23] [15]

[23]

[27]

[31]

3 Circadian Clock and Metabolic Diseases

3.2.1

45

Circadian Clock and Glucose Metabolism

The level of blood glucose depends on the balance between glucose input (from food, glycogenolysis, and gluconeogenesis) and glucose utilization (for energy production). Liver and pancreas are the most important organs in controlling blood glucose levels. The liver plays a key role in glucose homeostasis by storing (glycogenesis) and releasing (glycogenolysis and gluconeogenesis) glucose depending on the body’s need. Through these processes, the liver ensures that blood glucose levels remain steady after meals and during sleep. Pancreas helps to maintain the body’s blood glucose balance. β-cells in the pancreatic islets regulate insulin output to reduce blood glucose, whereas α-cells synthesize and secrete glucagon that elevates the blood glucose. The blood glucose level is controlled by the circadian clock system though regulating multiple processes such as glucose production (e.g., gluconeogenesis), utilization (e.g., glycogenesis), insulin sensitivity, and pancreatic α/β-cell function (Fig. 3.1). The circadian clock genes (e.g., CLOCK, BMAL1, CRYs, and REV-ERBα) regulate glucose level in a gene-specific manner. Disruption of Clock and Bmal1 shows impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets, resulting in hypoinsulinemia and diabetes in mice [25]. Conditional ablation of pancreatic Clock causes diabetes mellitus due to defective β-cell function at the very early stage of stimulus-secretion coupling [25]. The defective β-cell function is supported by diminished insulin secretory responses in pancreatic clock mutant mice [25]. Liver-specific Bmal1 mutant mice exhibit hypoglycemia during the fasting period due to increased glucose clearance [32]. Clock mutation dampens the hepatic glycogen content, and the circadian expression of glycogen synthase 2 that is the rate-limiting enzyme of glycogenesis in the liver. Luciferase reporter assays reveal that glycogen synthase 2 is transcriptionally activated by CLOCK [33]. Further, CLOCK/BMAL1 binds to the sirtuin 1 (SIRT1) promoter to enhance its expression and regulates hepatic insulin sensitivity [34]. Cry1 and Cry2 double knockout mice exhibit elevated blood glucose in response to acute feeding after an overnight fast and show reduced glucose clearance in the glucose tolerance test [20]. This is explained by the fact that CRYs compete with glucocorticoids for the glucocorticoid response element in the PEPCK promoter to regulate the conversion of energy substrates to glucose [15]. Moreover, polymorphisms in the core clock genes (e.g., CLOCK and CRY1) are linked to defects in glucose homeostasis and the susceptibility to type 2 diabetes (T2D) [35, 36]. REV-ERBα is implicated in glucose homeostasis and diabetes development due to its critical role in regulation of gluconeogenesis and pancreatic α/β-cell functions. Activation of REV-ERBα by an agonist reduces the levels of cellular and plasma glucose [15, 37, 38]. Consistently, Rev-erbα-deficient mice show increased plasma glucose levels [26, 39]. Yin et al demonstrate that REV-ERBα modulates glucose metabolism through regulating gluconeogenic rate-limiting enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6pase) in human

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hepatoma cells and in primary mouse hepatocytes [26]. In addition to the gluconeogenesis, REV-ERBα has a regulatory role in the functions of pancreatic α and β-cells. At high glucose concentrations, REV-ERBα down-regulates glucoseinduced insulin secretion in β-cells probably via modulation of the exocytotic process [40, 41]. At low glucose levels, REV-ERBα promotes low glucose-induced glucagon secretion in pancreatic α-cells through AMPK/Nampt/Sirt1 pathway [27, 42]. Moreover, REV-ERBα enhances the survival and activity of β-cells under diabetogenic conditions [43]. Accordingly, REV-ERBα can be targeted to alleviate glycemia disorders and diabetes [27, 42, 44]. In addition to regulating glucose levels, the circadian clock components (e.g., REV-ERBα and BMAL1) are implicated in the regulation of glucose rhythm. Blood and intracellular glucose oscillate in a circadian time-dependent manner [45, 46]. Up-regulation of REV-ERBα by MYC (a proto-oncogene and bHLH transcription factor) leads to a reduced level of BMAL1 and loss of glucose rhythmicity [47]. Cyclin-dependent kinase 1 (CDK1)-FBXW7 pathway promotes REV-ERBα degradation in mouse liver, disrupting the circadian rhythmicity in glucose metabolism [48].

3.2.2

Circadian Clock and Lipid Metabolism

Lipids are a family of organic compounds and are responsible for a variety of physiological functions in the body. Lipidomic analysis reveals that about ~17% of lipids (particularly triglycerides) in mouse liver are oscillating with a peak during the subjective light phase [49]. Triglyceride represents the main lipid component of dietary fat and fat depots in animals [50]. It is an ester derived from glycerol and three fatty acids. Triglycerides are utilized by the peripheral cells either as a direct source of energy or as an energy store in the adipose tissue. However, a high level of triglycerides increases the risks of heart diseases and stroke, thus controlling triglycerides to a low level is beneficial. The glycerol-3-phosphate pathway is the predominant biosynthesis pathway for triglycerides in the liver (Fig. 3.2a). The first and key rate-limiting step is the acylation of glycerol 3-phosphate to lysophosphatidic acid (LPA) by glycerol-3-phosphate acyltransferase (GPAT) enzymes [51]. Multiple hepatic enzymes (e.g., GPAT2, AGPAT1, AGPAT2, LPIN1, LPIN2, DGAT2, and PNPLA3) involved in triglyceride biosynthesis oscillate in a circadian time-dependent manner [51]. These enzymes synergically generate the circadian oscillation in triglycerides in the liver [51]. In addition to biosynthesisrelated enzymes, the level of triglycerides is also dependent on lipoprotein lipases (located on the walls of blood vessels) that break down triglycerides into free fatty acids and glycerol. There are also a number of regulatory factors for lipid metabolism. For example, ApoC-III is a key regulator of triglyceride metabolism by preventing catabolism of triglyceride-rich particles [52]. The adipocyte fatty acidbinding protein AP2 is a small carrier protein that binds to fatty acids and strongly

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A

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Glycerol-3-phosphate

Gpat2 GPAT

B

Lysophosphatidic Acid

Agpat1/2 AGPAT Triglycerides

Phosphatidate

Lipin1/2 Lipin

PERs

Gpat2, Agpat2, Lpin1/2, Dgat2, and Pnpla3

Diacylglycerol

Dgat2

LIPA DGAT

Pnpln3

PNPAL3

Triglycerides

Fig. 3.2 Role of PERs in triglyceride metabolism. (a) Major pathway for triglyceride biosynthesis (glycerol-3-phosphate pathway) and triglyceride catabolism. Some triglyceride-related genes (oscillating genes indicated in the graph) are under control of circadian clock. GPAT Glycerol-3phosphate acyltransferase, AGPAT 1-acylglycerol-3-phosphate acyltransferase, DGAT diacylglycerol acyltransferase, PNPLA3 patatin-like phospholipase domain containing 3, LIPA lysosomal acid lipase. (b) A schematic model depicting the circadian regulation of triglycerides by PERs

affects lipid homeostasis. Elovl3 (elongation of very long-chain fatty acids 3) plays a role in fatty acid chain elongation and formation of neutral lipids [51]. There is mounting evidence that circadian clock components (e.g., BMAL1, CLOCK, PERs, CRYs, and REV-ERBα) regulate lipid metabolism and related disorders (e.g., hyperlipidemia and obesity). Ablation of the single clock gene results in impaired lipid metabolism and altered body weight. For instance, Bmal1 or Clock knockout leads to hyperlipidemia in mice [21, 53]. Lack of Bmal1 alters the expression of lipid metabolism-related genes (e.g., lipoprotein lipases, the enzymes that degrade circulating triglycerides) and reduces fat storage [19]. Likewise, Clock mutant mice fed either a regular or high-fat diet show a significant increase in body weight, displaying altered diurnal rhythms in Per2 and metabolic genes (e.g., orexin and ghrelin) [21]. When maintained in a 24 h light/dark cycle and fed a chow diet, Pers-deficient mice are significantly heavier, but Cry mutants display a reduced body weight relative to wild-type mice at early ages [54]. Per1/2 ablation alters the expression profiles of enzymes (e.g., Gpat1/2, Agpat2, Lpin1/2, Dgat2, Lipa, and

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Pnpla3) involved in biosynthesis of triglycerides (Fig. 3.2b) [51]. A mechanistic study reveals that PER2 interacts with PPAR-γ via the PPAR-γ A/B domain containing a serine residue and blocks PPAR-γ recruitment to the promoters of target genes (e.g., Ap2, encoding a carrier protein for fatty acids) to promote lipogenesis [55]. Rev-erbα-deficient mice exhibit a defect in lipid metabolism, causing increases in triglycerides and free fatty acids in the liver [19, 34, 41]. Consistently, activation of REV-ERBα results in reduced triglyceride and free fatty acids in mice [23, 26]. The lipid-lowering effect of REV-ERBα is associated with transcriptional repression of ApoC-III and Elovl3 [23, 24]. Adipose tissue comprises about 20–25% of total body weight in healthy people, and its main role is to store energy in the form of lipids. In mammals, adipose tissue is divided into two functionally distinguishable classes: white adipose tissue (WAT) is to store energy, while brown adipose tissue (BAT) dissipates energy and generates heat. Circadian clock plays a significant role in adipogenesis in both WAT and BAT. Bmal1 deletion promotes the accumulation of triglycerides in WAT, leading to increased adiposity and adipocyte hypertrophy [56]. However, Bmal1 knockout in mice and adipocyte-selective inactivation increase brown fat mass and cold tolerance [57]. BMAL1 primarily regulates the canonical Wnt cascade in WAT, whereas it regulates the TGF-β pathway in BAT [58]. In addition, Per2 knockout in mice alters fatty acid oxidation and adipocyte morphology in WAT [24]. PER2 indirectly regulates lipid metabolism in WAT by a protein-protein interaction with PPARγ [24]. Consistent with the findings in animals, polymorphisms of clock genes are associated with predisposition to obesity. CLCOK polymorphisms may be protective from the development of obesity [37, 59]. PER2 polymorphisms rs2304672C > G and rs4663302C > T are associated with abdominal obesity [60]. The REV-ERBα rs2071427 polymorphism modulates body fat mass in both adults and adolescents [61]. Another polymorphism rs2314339 (in the intron of REV-ERBα) was associated with obesity in two cohorts from the Mediterranean and North American populations [62]. Recently, REV-ERBα polymorphism rs939347 is shown to modulate body fat mass in men, suggesting a gender-specific role of REV-ERBα in the development of obesity [63].

3.2.3

Circadian Clock and Cholesterol Metabolism

Cholesterol level mainly depends on the biosynthesis and elimination processes. Circadian clock regulates cholesterol homeostasis through modulating enzymes involved in these two processes. HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and CYP7A1 (cholesterol 7α-hydroxylase) are the rate-limiting enzymes for cholesterol biosynthesis and catabolism (or biosynthesis of bile acids), respectively. CLOCK protein participates in circadian regulation of cholesterol homeostasis in the liver of mice fed a diet containing high cholesterol and cholic acid [18]. Cholesterol is elevated in Clock mutant mice, which may be caused by reduced expressions of

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cholesterol-related genes such as Hmgcr, Cyp7a1, and Ldlr (low-density lipoprotein receptor) [18]. REV-ERBα is initially shown to regulate cholesterol catabolism and hypercholesteremia via a positive control of CYP7A1 [64, 65]. However, a consensus is still not reached regarding the mechanisms of REV-ERBα action on CYP7A1. REV-ERBα may regulate CYP7A1 through multiple pathways (e.g., E4BP4/SHP, INSIG2/SREBP, and LRH-1) [66]. Additionally, the effects of REV-ERBα on cholesterologenesis may involve the modification of cholesterol biosynthesis-related genes such as Hmgcr [57].

3.2.4

Circadian Clock and Amino Acid Metabolism

Amino acids (AAs) are the building blocks of proteins. AA and their metabolites (e.g., nitric oxide, polyamines, glutathione, taurine, thyroid hormones, and serotonin) are essential to human health. However, excessively elevated AAs and their metabolites (e.g., homocysteine and asymmetric dimethylarginine) in blood are pathogenic factors for neurological disorders, oxidative stress, and cardiovascular diseases [29, 30]. Many amino acids (e.g., alanine, leucine, isoleucine, and valine) in murine blood, liver, and/or muscle show 24-h oscillations, with higher levels during the dark phase and lower levels during the light phase [67, 68]. Circadian rhythms are noted for four AAs (i.e., ornithine, arginine, isoleucine, and proline) in human blood, which are shifted during a 24 h constant routine that followed a 3-day simulated night-shift schedule [69]. REV-ERBα plays a crucial role in homocysteine (a sulfur containing AA) metabolism and ammonia clearance [70]. Homocysteine is proceeded through two major pathways: remethylation to methionine catalyzed by BHMT (betaine homocysteine methyltransferase), and a two-step transsulfuration to cysteine catalyzed by CBS (cystathionine β-synthase) and CTH (cystathionine γ-lyase) [71]. Following use of amino acids, organisms are required to detoxify the byproducts such as ammonia. Ammonia is cleared mainly through conversion to urea [by the urea cycle consisting of multiple enzymes including ARG1 (arginase 1), CPS1 (carbamoyl-phosphate synthase 1) and OTC (ornithine transcarbamylase)] in the liver. REV-ERBα regulates homocysteine catabolism through direct transrepression of Bhmt, Cbs, and Cth, and ammonia clearance through inhibition of C/EBPα (CCAAT/enhancer-binding protein α) transactivation of Arg1, Cps1, and Otc [31]. It is proposed that targeting REV-ERBα represents a new approach in the management of homocysteine- and ammonia-related diseases [31]. The CLOCK polymorphism rs1801260 is associated with reduced plasma homocysteine, suggesting a close relationship between human CLOCK gene and homocysteine homeostasis [72]. Circadian clock may indirectly regulate AA metabolism via krüppel-like factor 15 (KLF15) [71]. KLF15 is transcriptionally regulated by the CLOCK/BMAL1 heterodimer via four E-box binding motifs. Klf15-null mice exhibit more severe hyperammonemia with impaired ureagenesis, suggesting regulation of urea

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synthesis by KLF15. This regulation effect is attained via a direct action on OTC [71]. Additionally, KLF15 regulates AA metabolism through alanine transaminase (ALT) and branched-chain transaminase (BCAT2) [71]. The nuclear receptor small heterodimer partner (SHP) and forkhead box A1 (FOXA1) contribute to homocysteine homeostasis in mice [31]. SHP is a circadian output protein, closely associated with several circadian clock components (e.g., Rev-erbα) [73]. Disruption of Shp in mice alters the temporal expression of homocysteine-related genes such as Bhmt and Cth. Mechanistically, SHP inhibits the transcriptional activation of Bhmt and Cth by FOXA1 [74].

3.2.5

Circadian Clock and Bilirubin Metabolism

Bilirubin, an end-product of heme catabolism, is a potentially toxic endogenous compound in the body [75]. High levels of free bilirubin are deleterious, causing jaundice and brain damage. Unconjugated bilirubin (UCB) is transported into the hepatocytes by the organic anion transporting polypeptides. In hepatocytes, UCB is metabolized by UDP-glucuronosyltransferase 1A1 (UGT1A1) to bilirubin monoand di-glucuronides (i.e., conjugated bilirubin, CB). CB is then excreted into the bile by the efflux transporter multidrug-resistance protein 2 (MRP2) and into the blood circulation by multidrug-resistance protein 3 (MRP3) for renal clearance. UCB level displays a significant diurnal fluctuation in wild-type mice with a nadir value at ZT14. Bmal1 ablation increases plasma UCB in mice and abolishes its circadian rhythm. Also, Bmal1 ablation sensitizes mice to chemical-induced hyperbilirubinemia. Mechanistically, BMAL1 trans-activates mouse Ugt1A1 and Mrp2 via the E-boxes in their promoter region. Moreover, bilirubin itself serves as an “enhancer” for BMAL1 regulation of bilirubin detoxification through antagonism of REV-ERBα, constituting a feedback mechanism in bilirubin detoxification [22].

3.2.6

Circadian Clock and Bone Metabolism

Bone remodeling is characterized by two successive phases: resorption of preexisting bone by osteoclasts followed by de novo bone formation by the osteoblasts [74]. Bone resorption and formation occur in a balanced manner to maintain constant bone mass. Both processes are known to be regulated by circadian clock. BMAL1 regulates bone metabolism, however, the regulatory effects and underlying mechanisms remain inconclusive. In the report of Xu et al, osteoclast-specific deletion of Bmal1 leads to a high bone mass and reduced osteoclast differentiation in mice [76]. Osteoclastic BMAL1 may regulate bone resorption through interacting with the steroid receptor coactivator (SRC) family and binding to Nfatc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1) promoter [77]. By contrast, Samsa et al report that Bmal1 deficiency causes a low bone mass probably

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through control of mesenchymal stem cell differentiation into mature osteoblasts [22]. Per1/2 or Cry1/2 double knockout mice show an increased rate of bone deposition and a high bone mass [78]. Mechanistically, Pers deficiency in osteoblasts results in elevated G1 cyclin expression that leads to a shortening of the cell cycle and increased osteoblast cell proliferation [79]. Activation of REV-ERBα suppresses receptor activator of nuclear factor κB ligand (RANKL)-induced podosome belt formation and inhibits osteoclast bone resorption, thereby ameliorating ovariectomy-induced bone loss [77]. Furthermore, REV-ERBα regulates osteoclastogenesis via inducing an intracellular lipid-binding protein named FABP4 (fatty acid-binding protein 4, also known as aP2) [80]. In addition, REV-ERBα inhibits osteogenesis by repressing the expression of bone sialoprotein in bone mesenchymal stem cells [81].

3.2.7

Targeting Clock Genes to Treat Metabolic Diseases

REV-ERBs and RORs are circadian clock components that can be targeted by small molecules [3, 79]. Recent years have witnessed the discovery of an array of new REV-ERBs and RORs ligands including synthetic and natural compounds, most of which have pharmacological activities in vivo (Table 3.2) [82]. These ligands can be used to probe the functions of REV-ERBs and RORs in cell and animal studies. Moreover, pharmacological targeting of circadian clock components by these ligands provides new preventive and therapeutic strategies for metabolic diseases. For example, heme (a REV-ERBs agonist) is an important signaling molecule for induction of adipogenesis [80]. Administration of the RORα inverse agonist SR3335 reduces plasma glucose in mice, which is attributed to decreased gluconeogenesis [83].

3.3

Feedback of Metabolism on the Circadian Clock

There is accumulating evidence that metabolism is not only an output of circadian clock but also provides essential inputs to the circadian clock [13]. Metabolic diseases are shown to be a contributing factor to circadian clock dysfunction. Metabolic signals (metabolites and hormones) can affect the circadian clock system, altering the circadian parameters (e.g., amplitude, period, and phase) and clock gene expression.

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Table 3.2 A list of ligands for REV-ERBs and RORs Ligand Heme GSK4112 SR8278 SR9009/SR9011 ENA_T5382514 ENA_T5445822 ENA_T5603164 GSK2945* GSK0999/5072/2667 ARN5187 Chelidamic acid GSK1362 SR12418 Bilirubin Berberine Puerarin Cholesterol/cholesterol sulfate All-trans retinoic acid T0901317

Target REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs REVERBs RORs RORs RORs

SR1078 7α-hydroxycholesterol/7β-hydroxycholesterol/ 7-ketocholesterol 20α-hydroxycholesterol/22Rhydroxycholesterol/25-hydroxycholesterol ML209

RORs RORs

RORs

Digoxin

RORs

RORs

Type of action Agonist

Year 2007

Reference [82]

Agonist

2008

[84]

Antagonist

2011

[85]

Agonist

2012

[26]

Agonist

2012

[86]

Agonist

2012

[87]

Antagonist

2012

[87]

Agonist/ antagonist Agonist

2013/ 2018 2013

[88]/[67] [89]

Antagonist

2015

[90]

Agonist

2018

[87]

Inverse agonist Agonist

2018

[89]

2018

[91]

Antagonist

2019

[22]

Agonist

2019

[92]

Antagonist

2019

[93]

Agonist Antagonist Inverse agonist Agonist Inverse agonist Agonist

2002 2003 2010

[94] [95] [96]

2010 2010

[97] [98]

2010

[99]

2010

[100]

2011

[101]

Inverse agonist Inverse agonist

(continued)

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Table 3.2 (continued) Ligand SR3335/ML176

Target RORs

SR1001

RORs

Ursolic acid

RORs

Compound 1a/1b/1c Inhibitor Ύ

RORs RORs

SR2211

RORs

SR1555

RORs

Neoruscogenin/(25S)-ruscogenin XY011/8 k GSK805 N-(4-aryl-5-aryloxy-thiazol-2-yl)-amides

RORs RORs RORs RORs

Biaryl amides GN-3500

RORs RORs

Pyrazole-containing benzamides

RORs

XY018

RORs

LYC-53772/LYC-54143 JNJ-54271074

RORs RORs

4OH-ATRA/4 K-ATRA D3 hydroxy-derivatives

RORs RORs

Compound 1

RORs

AZ5104 N-sulfonamide-tetrahydroquinolines

RORs RORs

3.3.1

Type of action Inverse agonist Inverse agonist Inverse agonist Agonist Inverse agonist Inverse agonist Inverse agonist Agonist Antagonist Antagonist Inverse agonist Inhibitor Inverse agonist Inverse agonist Inverse agonist Agonist Inverse agonist Agonist Inverse agonist Inverse agonist Agonist Inverse agonist

Year 2011

Reference [85]

2011

[102]

2011

[103]

2012 2012

[104] [105]

2012

[106]

2012

[107]

2014 2014 2014 2015

[105] [108] [109] [110]

2015 2015

[111] [112]

2015

[113]

2016

[114]

2016 2016

[115] [116]

2017 2017

[117] [118]

2018

[119]

2019 2020

[120] [121]

Metabolic Diseases Lead to Circadian Dysfunction

The rhythms in clock genes are blunted in peripheral leucocytes in T2D patients [11]. In particular, the amplitudes of PER1 and PER3 are diminished in patients with diabetes [11]. The peripheral oscillators show phase shift in T2D mouse model [12]. The rhythm of Per2 is severely diminished, and Bmal1 is phase advanced in the

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liver of diabetic mice [12]. Similar observations are observed in rodents with obesity [122, 123]. For example, high-fat diet lengthens the free-running period and tissuespecifically affects clock gene expression in the mediobasal hypothalamus, fat, and liver [124]. In high-fat diet treated mice, Clock and Bmal1 rhythms are significantly attenuated in both fat and liver [124]. This is in accordance with the finding that diurnal patterns of metabolic markers and transcription networks are dysregulated upon high-diet food treatment [124]. However, the exact mechanism that links metabolic diseases to the circadian clock is yet to be defined.

3.3.2

Metabolic Signals Act as Synchronization Cues (Zeitgebers)

In addition to the light (the predominant zeitgeber), feeding represents a crucial time cue driving peripheral oscillators. A 24-h metabolomics study reveals circadian oscillations in many metabolites in mice [70]. High-fat diet disrupts circadian rhythms in these metabolites in a tissue-specific manner [70]. Both feeding time and food compositions show significant effects on circadian clock. Feeding time can reset circadian clock in peripheral organs. Wehrens et al. report that a 5-h delay in meals exerts a variable influence on participants’ physiological rhythms, with a 0.97h delay in PER2 expression in white adipose tissue [125]. Plasma glucose rhythm is delayed by 5.69-h, indicating that molecular clocks are regulated by feeding time [126]. High-fat diet generates a profound reorganization of metabolic pathways, leading to extensive remodeling of the liver clock. The high-fat diet dampens CLOCK/BMAL1 recruitment to target chromatin sites, and activates surrogate pathways through the transcriptional regulator PPAR-γ. In addition, protein-only diet is an entraining factor of the liver clock [124]. This effect is attained through regulation of glucagon secretion [127]. A variety of feeding-related nutrients, metabolites, and hormones (e.g., glucose, insulin, glucagon, melatonin, ghrelin, FGF21, and AAs) can entrain the circadian clock [13]. Glucose is connected to the circadian clock through O-GlcNAcylation and the pentose phosphate pathway [128, 129]. O-GlcNAcylation of BMAL1, CLOCK, and PER2 results in an alteration in the period length of circadian clock [130, 131]. Inhibition of the pentose phosphate pathway lengthens the oscillation period of BMAL1:LUC (a fusion protein of BMAL1 and luciferase) by 3 h in human U2OS cells, due to changes in CLOCK–BMAL1 binding to target genes and p300dependent histone acetylation [126]. The insulin signal is involved in regulation of the peripheral clocks. Insulin induces postprandial Akt-mediated Ser42-phosphorylation of BMAL1 to promote its dissociation from DNA, interaction with 14–3-3 protein, and subsequently nuclear exclusion, resulting in suppression of BMAL1 transcriptional activity [127]. Resetting of mouse islet clocks by glucagon is cellspecific [128]. Glucagon induces extensive oscillations in PER2 in β-cells, but not in α-cells [132]. The synchronizing effect of glucagon is dose-dependent and mediated

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by the adenylate cyclase signaling cascade [132]. A single melatonin injection results in a phase shift in Bmal1 and Rev-erbα in rat SCN [129]. Melatonin can also act directly on proteasomes, which regulate the expression of clock genes [133]. Moreover, ghrelin (the “hunger hormone”) induces a phase advance in circadian rhythms in cultured SCN slices and explants [134]. In addition to feeding, other zeitgebers such as temperature, oxygen, and carbon monoxide regulate peripheral oscillators [132]. The synchronization by temperature is likely driven by the temperature sensor proteins comprising cold-inducible RNA-binding protein 1 (CIRPB) and heat-shock factor 1 (HSF1). Cold temperature induces CIRBP expression to modulate pre-mRNA maturation of Clock [135, 136]. An increase in body temperature can activate HSF1, which transcriptionally activates Per2 gene [137]. Rhythmic oxygen synchronizes the circadian clock in a hypoxia-inducible factor 1α (HIF1α)-dependent manner. Modulation of ambient oxygen level accelerates the adaptation to jet lag [138]. HIF1α activation increases the period length, probably through physical interactions between HIF1α and BMAL1 [13, 139]. Carbon monoxide attenuates DNA binding ability of CLOCK–BMAL1 and NPAS2–BMAL1, probably via coordination by a heme molecule bound to NPAS2 and CLOCK [140].

3.4

Concluding Remarks

Circadian clock has been implicated in regulation of an array of metabolic diseases. In turn, metabolic cues can feedback to the circadian clock by affecting the rhythmic expression and activity of clock components. The strong interplay between circadian clock and metabolism may provide circadian clock with the necessary flexibility to adjust physiology to the metabolic requirements at the cell, tissue, and organism levels. Novel ligands targeting the circadian clock components such as REV-ERBs and RORs are being developed to manage metabolic diseases. It is envisioned that ligands with improved pharmacokinetics and reduced toxicity may enter clinical trials in the near future.

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Chapter 4

Circadian Clock and CYP Metabolism Tianpeng Zhang, Fangjun Yu, Lianxia Guo, and Dong Dong

Abstract Cytochromes P450 (CYPs), a superfamily of hemoproteins, have monooxygenase activity and are involved in xenobiotic detoxification and lipid metabolism. Circadian clock is known to impact drug efficacy and toxicity through regulating metabolism and pharmacokinetics. Ongoing research has begun to unveil the molecular mechanisms by which clock genes regulate circadian CYP expression and chronopharmacokinetics. On the other hand, CYP activities affect the circadian clock by modulating melatonin metabolism, glucocorticoid, and NAPDH synthesis. This chapter provides an overview of current understanding of how the circadian clock regulates the expression and activities of CYP enzymes to affect xenobiotic detoxification and lipid metabolism, and how CYP activities affect circadian rhythms. Keywords Circadian clock · Metabolism · Cytochrome P450 · Chronopharmacology

4.1

Introduction

In mammals, circadian clock influences homeostasis in a broad range of physiological processes, including glucose and lipid metabolism, endocrine hormone secretion, renal and cardiovascular activities [1, 2]. Disruption of circadian coordination can lead to hormonal imbalance, psychological and sleep disorders, cancer proneness, and reduced life span [3–5]. As circadian clock is so fundamental to mammalian physiology, it is expected that circadian rhythms are involved in regulation of

T. Zhang · F. Yu · L. Guo Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China D. Dong (*) School of Medicine, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_4

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pharmacology and drug effects. Indeed, many studies have demonstrated that circadian clock plays an important role in determining chronopharmacokinetics and chronopharmacodynamics [6]. Therefore, circadian clock has a substantial effect on drug efficacy and toxicity, and this effect should be considered in drug development and clinic settings to achieve the highest drug efficacy and minimal toxicity [6, 7]. Radzialowski and Bousquet first reported a circadian variation in drug metabolism in 1968. Since then, accumulating studies indicate that dosing time-dependent pharmacokinetics and drug effects are associated with circadian oscillations in drug metabolism in humans and rodents [8, 9]. Xenobiotic (including drugs and environmental toxicants) detoxification is generally divided into three phases, namely, phase I modification, phase II conjugation, and phase III excretion [10]. Cytochromes P450 (CYPs) are responsible for phase I metabolism of up to 75% of clinically used drugs [11]. Recent studies demonstrate that many CYP enzymes oscillate in a circadian time-dependent manner, indicating a role of CYPs in circadian xenobiotic metabolism [6, 9, 12]. This chapter provides an overview of current understanding of how the circadian clock regulates the expression and activities of CYP enzymes to affect xenobiotic detoxification and lipid metabolism, and how CYP activities affect circadian rhythms.

4.2

CYP Superfamily

CYP enzymes have been described as predominant hepatic enzymes that metabolize drugs, arachidonic acid, steroids, fat-soluble vitamins, carcinogens, pesticides, and many other types of chemicals [13, 14]. The most common reaction catalyzed by CYPs is the monooxygenase reaction in which one oxygen atom from O2 is inserted into the substrates. Whole genomic analysis reveals that there are 57 functional CYP genes in human genome, and 108 functional Cyp genes in mouse genome (Table 4.1) [15]. Based on unweighted pair group analysis, there are 34 orthologous pairs of CYP genes between mice and humans (Table 4.1) [15]. Human or mouse CYP genes are grouped into 18 families according to their sequence similarity (Table 4.1) [15]. CYP1, CYP2, and CYP3 families are primarily responsible for metabolism of clinical drugs (Table 4.1). The CYP4 family mainly participates in fatty acid metabolism (Table 4.1). Other important CYP enzymes include the CYP7A1 (involved in bile acid biosynthesis), and CYP11 and CYP17 enzymes (involved in steroid biosynthesis) (Table 4.1). RNA-seq analysis of mouse tissues indicate that 52% of the Cyp genes are mainly expressed in the liver, 10% in the kidney, 10% in the intestine, 10% in the testis, 5% in the lung, and night Systemic exposure ZT2 >ZT14; toxicity ZT2 >ZT14 Chronopharmacokinetic and chronotoxicity abolished Systemic exposure ZT2 > ZT14; Toxicity ZT2 < ZT14 Chronopharmacokinetic and chronotoxicity abolished Toxicity ZT2 < ZT14 Toxicity decreased; chronotoxicity lost Toxicity decreased; chronotoxicity lost Reduced toxicity 6-Hydroxychlorzoxazone (metabolite) dark phase > light phase Susceptibility dark phase > light phase Systemic, kidney and adipose tissue exposure ZT3 > ZT19 Systemic exposure ZT2 > ZT14; hepatotoxicity ZT2 > ZT14 Chronotoxicity abolished Systemic exposure ZT2 > ZT14; toxicity ZT2 > ZT14 Chronopharmacokinetic and chronotoxicity abolished Sleep time ZT2 > ZT14; clearance ZT2 < ZT14 Decreased clearance; prolonged sleep time

Reference [41] [22]

[22] [22]

[22] [21] [42] [21] [43] [44]

[45] [46] [47]

[47] [23, 48]

[23, 48] [49] [49]

fluvoxamine [38–40]. Therefore, it is not surprising that the metabolism and/or toxicity of these drugs may be dosing time-dependent [41]. For example, the plasma level of theophylline is greater when the drug is administered in the morning than in the evening (Table 4.3). This is why theophylline causes a higher rate of mortality in

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the light phase than in the dark phase [50]. Per2 ablation abrogates the rhythm in Cyp1a2 expression, thereby eliminating the time-dependency of acetaminopheninduced hepatotoxicity [43]. This indicates regulation of circadian Cyp1a2 expression by Per2. Circadian expression of Cyp1a2 is also regulated by Shp, which is a circadian gene whose expression is under the control of Bmal1 and Clock/Npas2. Shp ablation blunts the rhythmic expression of Cyp1a2 and exacerbates theophylline-induced toxicity [21]. Mechanistic studies reveal that SHP represses DEC2/HNF1α axis to upregulate Cyp1a2 [21].

4.4.3

CYP2A4/5

CYP2A4/5 are constitutively expressed in the liver, kidney, lung, and nasal mucosa [34]. Hepatic Cyp2a4/5 are expressed at a higher level in female mice than in male mice [51]. Cyp2a4/5 mRNAs in mouse liver oscillate in a circadian time-dependent manner that peaks at around ZT10 [21, 22]. Likewise, CYP2A4/5 proteins show significant diurnal rhythms, but the phase is delayed 12–16 h relative to the mRNA rhythm [21]. CYP2A5, a mouse enzyme orthologous of human CYP2A6, catalyzes a number of toxicologically important reactions, including the metabolism of coumarin, nicotine, cotinine, and aflatoxin B1. Coumarin 7-hydroxylation has been used as a biomarker to probe the activities of CYP2A5 and CYP2A6. Consistent with circadian CYP2A4/5 proteins, the formation of 7-hydroxycoumarin is more extensive at dosing time of ZT2 than that at ZT14 [52]. Zhao et al. identified CLOCK as a critical regulator of CYP2A4/5 rhythms and of coumarin chronotoxicity [22]. Clock ablation disrupts diurnal expressions of CYP2A4/5 and sensitizes mice to coumarininduced toxicity (Table 4.3) [22]. Multiple studies indicate that Dbp, a PAR (proline and acidic amino acid rich) basic leucine zipper transcription factor, is a major factor controlling the circadian expressions of CYP2A4/5 in mouse liver [9, 53, 54]. This is because (1) the promoters of Cyp2a4/5 genes contain high-affinity binding sites (D-box) for DBP, and (2) circadian rhythms in hepatic CYP2A4/5 are blunted in Dbp knockout mice [53]. However, the circadian rhythm in CYP2A5 expression is not completely eliminated in Dbp / mice, indicating involvement of other factors in controlling CYP2A5 rhythm. DBP and E4BP4 are known to play an antagonist role in regulating gene transcription through competitive binding to the same D-box. Contrasting with the activation action of DBP on Cyp2a4/5, E4BP4 represses the transcription of Cyp2a4/5 [21]. SHP dose-dependently antagonizes the repressive action of E4BP4, potentially contributing to Cyp2a4/5 rhythms [21]. Further, CLOCK protein is reported to control the diurnal expressions of Cyp2a4/5 by direct binding to E-box elements ( 1706/ 1700 bp) in their promoter regions or by regulating DBP expression [22]. Additionally, Deng et al. report that PPARγ knockdown blunts the rhythmicity in Cyp2a5 mRNA in serum-shocked Hepa-1c1c7 cells [51]. Mechanistic studies indicate that PPARγ, as a transcriptional activator, regulates the circadian expression of Cyp2a5 by binding to specific PPARγ response element (PPRE,

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Fig. 4.3 Molecular mechanisms for rhythmic Cyp2a4/5 expression

1418/ 1396 bp) [52]. Taken together, rhythmic expressions of CYP2A4/5 are generated from transcriptional regulation by D-box-, E-box-, and PPRE-binding proteins (Fig. 4.3).

4.4.4

CYP2B10

CYP2B10 is expressed in the liver, kidney, lung, brain, small intestine, and testis, with higher expression in the liver and kidney. Cyp2b10 expression shows a gender difference (female >> male), particularly in mouse liver. Cyp2b10 mRNA displays a robust diurnal variation with a peak value at ZT18 in the liver and intestine of mice [9, 21, 22]. The amplitude of Cyp2b10 mRNA is at least tenfold in mice, which might be the largest for circadian CYP genes. However, the amplitude of CYP2B10 protein is much smaller (about twofold) [22]. Consistent with the protein levels, hepatic CYP2B10 activity toward the specific substrate pentoxyresorufin displays a circadian rhythm with a higher activity at ZT14 than at ZT2 [22]. Likewise, the plasma level of cyclophosphamide (a typical substrate of CYP2B10) is higher when the drug is administered at ZT2 than at ZT14 [22]. Accordingly, cyclophosphamideinduced toxicity is more severe at dosing time of ZT14 than at ZT2 (Table 4.3) [22]. Gachon et al. first reported that rhythmic expression of CYP2B10 is governed by three PAR bZip proteins (DBP, HLF, and TEF). The rhythms of Cyp2b10 are blunted, and circadian responses to pentobarbital (metabolized by CYP2B10) are abrogated in PAR bZip-deficient mice [9]. Mechanistic studies show that PAR bZip proteins regulate CYP2B10 expression through constitutive androstane receptor (CAR), which binds to phenobarbital-response element (PBRE) in the Cyp2b10 promoter [9]. REV-ERBα is identified as an important regulator in modulating CYP2B10 rhythm. This is supported by (1) Cyp2b10 promoter contains a

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Fig. 4.4 Molecular mechanisms for rhythmic Cyp2b10 expression

high-affinity binding site (RORE) for REV-ERBα, (2) circadian rhythm in CYP2B10 expression is blunted in the liver of Rev-erbα knockout mice, and (3) REV-ERBα mediates regulation of circadian Cyp2b10 expression by other genes such as Clock and Shp [21, 22]. Therefore, CYP2B10 rhythm is directly regulated by REV-ERBα through RORE cis-element and indirectly regulated by CLOCK/SHP/PAR bZip proteins through RORE or PBRE element (Fig. 4.4).

4.4.5

CYP2E1

Human CYP2E1 gene is localized on chromosome 10q26.3, consisting of nine exons and eight introns [55]. Unlike other CYP2 genes containing multiple closely related members, CYP2E1 is the only member of the CYP2E subfamily in humans, rats, and mice. CYP2E1 is highly expressed in the liver and constitutes 9% of the total CYP content of hepatic microsomes [51]. CYP2E1 mRNA in human and mouse liver shows a significant 24-h rhythm, and the level increases from the late light phase to the early dark phase [21, 56, 57]. CYP2E1 protein also displays a robust circadian rhythm with a peak value at ZT14 [21]. Likewise, the metabolism of 4-nitrophenol (a biomarker activity for CYP2E1) in liver microsomes are circadian time-dependent with a higher activity at ZT14 than at ZT2 [21]. Both human and mouse CYP2E1 metabolize a number of low molecular weight organic chemicals (e.g., carbon tetrachloride, chloroform, N-nitrosodimethylamine, and trichloroethylene) into carcinogens. It is not surprising that the toxicities of these chemicals are dosing timedependent due to the diurnal rhythm of CYP2E1 (Table 4.3) [45, 58]. CYP2E1 is also involved in metabolism of drugs such as chlorzoxazone, acetaminophen (APAP), and isoniazid. Consistent with circadian CYP2E1 expression, the AUC0–8 h of 6-hydroxychlorzoxazone, a metabolite generated from CYP2E1

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Table 4.4 CYP enzymes involved in circadian clock regulation of metabolism and metabolic diseases Metabolism or disease Bile synthesis

CYP CYP7A1

Bile synthesis

CYP7A1

Bile synthesis

CYP7A1

Bile synthesis

CYP7A1

Bile synthesis

CYP8B1

Bile synthesis

CYP8B1

Bile synthesis

CYP8B1

Alcoholic liver injury NASH

CYP2E1

Animal model Rev-erbα mice Shp / mice Per2 / mice Clock / mice Rorα / mice Rorγ / mice Shp / mice WT mice

CYP2E1

WT mice

NASH, type 2 diabetes Diabetes

CYP4A

WT mice

CYP4A

Pparα mice

/

/

Main finding Decreased bile acid level

Reference [24]

Increased synthesis of bile acids

[59]

Elevated bile acid level

[60]

Evaluated cholesterol level

[61]

Increased liver and serum cholesterol

[62]

Increased liver and serum cholesterol

[62]

Increased synthesis of bile acids

[59]

Induced ROS generation

[63]

Induced lipid peroxidation, oxidant stress and cellular toxicity Induced lipid peroxidation and oxidant stress Reduced lipid peroxidation

[63, 64] [64, 65] [66]

metabolism of chlorzoxazone, is significantly higher in the dark phase than in the light phase [44]. CYP2E1 converts APAP to the metabolite N-acetyl-p-benzoquinone imine (NAPQI), accounting for APAP hepatotoxicity. APAP hepatotoxicity displays significant 24-h rhythm (a lower hepatotoxicity of APAP at ZT2 than at ZT14) [21]. Ablation of clock genes (e.g., Bmal1, Per2, and Shp) abolishes the diurnal rhythms in CYP2E1 and APAP-induced chronotoxicity (Table 4.3) [21, 42, 43]. Additionally, CYP2E1 metabolizes ethanol and polyunsaturated fatty acids (e.g., linoleic acid and arachidonic acid) to generate ROS and to promote lipid peroxidation, oxidant stress, and cellular toxicity, thereby affecting the progression of alcoholic and non-alcoholic fatty liver diseases (Table 4.4) [63, 67]. Ablation of clock genes (e.g., Clock and Rev-erbα) induces hepatic steatosis [68]. Hence, it is speculated that clock genes prevent the progression of fatty liver to steatohepatitis partly through regulating CYP2E1 activity [69]. Multiple clock genes have been shown to regulate rhythmic expression of CYP2E1. Matsunaga et al. show that CRY1 regulates rhythmic expression of CYP2E1 through repression of HNF1α-mediated transactivation in humans and mice [56]. APAP-induced toxicity is attenuated and its rhythm is blunted in both Clock-deficient and Bmal1-deficient mice, indicating circadian regulation of Cyp2e1 by Clock and Bmal1 [49]. Supporting this, Matsunaga et al. found that CLOCK and

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Fig. 4.5 Molecular mechanisms for rhythmic Cyp2e1 expression

BMAL1 can enhance transcriptional activity of Cyp2e1 [56]. In addition, the nuclear receptor SHP (a target of BMAL1 and CLOCK/NPAS2) is a regulator of circadian CYP2E1 expression. This is evidenced by (1) rhythms of CYP2E1 mRNA and protein are blunted in Shp-deficient mice, and (2) SHP represses DEC2/HNF1α axis to upregulate Cyp2e1 [21]. Altogether, circadian expression of Cyp2e1 is indirectly regulated by clock genes (Cry1, Shp, and Dec2) through regulating HNF1α mediated transactivation (Fig. 4.5).

4.4.6

CYP3A11

CYP3A11 is expressed in the liver, intestine, kidney, brain, skeletal muscle, spleen, lung, and heart, with the highest expression in the liver [34]. Hepatic and intestinal Cyp3a11 mRNA show a robust circadian expression with a peak value at ZT6 [21, 23]. CYP3A11 protein and activity also display significant 24-h oscillations, but the phase of protein is delayed 12 h relative to the mRNA rhythm [21, 23]. Human CYP3A4 mRNA, an ortholog of mouse Cyp3a11, displays a circadian rhythm [31, 56]. Consistently, the metabolic activity of CYP3A4 in serum-shocked HepG2 cells oscillates according to the time with a period of about 24 h [31, 56]. CYP3A4 (CYP3A11) is most important drug-metabolizing enzyme. It is estimated that up to 50% of all drugs are metabolized by CYP3A4 [70]. Circadian expression of CYP3A4/CYP3A11 accounts for the chronopharmacokinetic behaviors of many drugs such as roscovitine, seliciclib, aconitine, hypaconitine, and brucine (Table 4.3) [23, 46, 48]. Sallam et al. found that the plasma level of roscovitine is 38% higher when dosing at ZT3 and elimination half-life is two times longer as compared to dosing at ZT19. Lin et al. and Zhou et al. observe dosing time-dependent toxicities for aconitine, hypaconitine, and brucine [23, 47, 48]. The toxicities of aconitine, hypaconitine, and brucine are more severe in the

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Fig. 4.6 Molecular mechanisms for rhythmic Cyp3a11 expression

light phase than in the dark phase [23, 48]. Interestingly, the chronotoxicity of aconitine, hypaconitine, and brucine depends on the circadian variations in CYP3A11 expression. Bmal1 ablation abrogates the rhythm of CYP3A11, thereby eliminating the time-dependency of aconitine and hypaconitine toxicity [48]. Npas2 ablation markedly downregulates CYP3A11 expression and activity, and abrogates their diurnal rhythms. This is accompanied by a loss in time differences in brucine pharmacokinetics and hepatotoxicity [47]. DBP regulates circadian expression of mouse Cyp3a11 by specific binding to a D-box (a motif for Dbp binding, located at 123/ 110 bp) in the promoter [71]. DBP transactivation of Cyp3a11 can be repressed by E4BP4 [72]. The antagonistic role of DBP and E4BP4 is confirmed by the study of Takiguchi et al. in which CYP3A4 is rhythmically expressed and the rhythmicity is coordinated by DBP and E4BP4 [31]. The authors identify a D-box (located at 66/ 14 bp region) in CYP3A4 promoter using luciferase reporter and electrophoretic mobility shift assays [31]. PPARα contributes to circadian expression of CYP3A4 because (1) PPARα is a known regulator of CYP3A4, and (2) PPARα (a target of BMAL1/CLOCK) expression exhibits a circadian rhythm [73]. Lin et al. identify BMAL1 as a critical regulator of CYP3A11 rhythm in the liver and intestine. Bmal1 deficiency decreases the expression and microsomal activity of CYP3A11, and blunts their circadian rhythms in the liver and intestine of mice [23]. Mechanistic studies show that BMAL1 activates Cyp3a11 transcription through DBP and HNF4α [23]. NPAS2 also participates in regulation of circadian CYP3A11 expression because Npas2 ablation markedly downregulates CYP3A11 expression and activity, and abrogates their diurnal rhythms [47]. Additionally, global deletion of Shp decreases CYP3A11 expression, and blunts its circadian rhythmicity. Further experiments reveal that SHP regulates Cyp3a11 through the DEC2/HNF1α axis [21]. Taken together, circadian CYP3A11/CYP3A4 expression is generated and maintained by D-box, PPRE, and Hnf1-RE binding proteins (Fig. 4.6).

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4.4.7

79

CYP4A10/14

CYP4A10 is predominantly expressed in the kidney and moderately expressed in the liver. Cyp4a10 and 4a14 mRNAs exhibit circadian rhythms in the liver, decreasing during the daytime and increasing during the nighttime with the lowest levels at ZT10 [21]. CYP4A10 and 4A14 proteins also show robust diurnal variations, but the phase of protein is delayed 12 h relative to the mRNA rhythm [21]. CYP4A10 and 4A14 metabolize arachidonic acid, lauric acid, and palmitic acid to generate 20-HETE, which is a critical modulator of renal function and blood pressure [74]. CYP4A10 and 4A14 catalyze lipid peroxidation and affect the level of reactive oxygen species (ROS) in mice [64]. Inhibition of CYP4A in mice reduces hepatic endoplasmic reticulum stress, apoptosis, insulin resistance, and steatosis to treat type 2 diabetes (Table 4.4) [65, 66]. Zhang et al. demonstrate REV-ERBα as a critical regulator of circadian expression of CYP4A10 and 4A14 [21]. The authors identify REV-ERBα binding sites in Cyp4a10 and 4a14 promoters ( 1103/ 1087 bp for Cyp4a10 and 1709/ 1693 bp for Cyp4a14) using luciferase reporter, electrophoretic mobility shift, and ChIP assays [21]. Furthermore, CYP4A10 and 4A14 are regulated by PPARα, whose expression exhibits a circadian rhythm [75, 76]. Additionally, SHP regulates the rhythmic expression of CYP4A10 and 4A14. Shp deletion blunts circadian rhythmicity in hepatic CYP4A10 and 4A14. Further experiments demonstrate that Cyp4a10 and 4a14 transcription are repressed by REV-ERBα and SHP inhibits REV-ERBα-mediated transrepression (Fig. 4.7) [21]. Taken together, rhythmic expressions of CYP4A10 and 4A14 are directly regulated by REV-ERBα/PPARα and indirectly regulated by SHP through REV-ERBα.

Fig. 4.7 Molecular mechanisms for rhythmic Cyp4a10/14 expression

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4.4.8

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CYP7A1

CYP7A1 is the rate-limiting enzyme in the biosynthesis of bile acids from cholesterol, and accounts for 75% (mice) to 90–95% (humans) of total bile acid synthesis [77]. Deficiency of CYP7A1 is associated with hypercholesterolemia, leading to cardiovascular and gallstone diseases [78]. CYP7A1 is exclusively expressed in the liver, and its expression oscillates in a circadian time-dependent fashion (higher expression levels in the dark phase with a peak level at ZT18) [24, 25]. Diurnal variations in CYP7A1 enzyme are associated with the circadian rhythms of bile acid synthesis and cholesterol [25]. Clock genes have been shown to regulate cholesterol and bile acid homeostasis through modulating Cyp7a1 activity (Table 4.4). Per1 and Per2 double knockout mice show elevated levels of serum and hepatic bile acids and cholestatic livers due to an abnormal expression of CYP7A1 [60]. Clock mutant mice show reduced and arrhythmic expression of Cyp7a1, as well as elevated cholesterol in the blood and liver [61]. Rev-erbα deficient mice display a lower synthesis rate and impaired excretion of bile acids into the bile and feces, due to a decreased expression of CYP7A1 [25]. The critical role of REV-ERBα in the control of cholesterol metabolism is further reinforced by the finding that treatment of hypercholesterolemia mice with synthetic small molecule agonists of REV-ERBα decreases the cholesterol level in the blood and liver [24]. Shp ablation causes abnormal accumulation of and increased synthesis of bile acids due to de-repression of CYP7A1 [59]. The mechanisms for circadian CYP7A1 expression are complex, involving multiple clock genes and nuclear receptors (Fig. 4.8). DBP amplifies the circadian rhythm of CYP7A1, and several DBP-responsive elements (D-box) in Cyp7a1 promoter have been identified [79]. Cyp7a1 transcription enhanced by DBP is strongly suppressed by E4bp4, which competitively binds to D-box. DEC2 represses

Fig. 4.8 Molecular mechanisms for rhythmic Cyp7a1 expression

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the transcription of Cyp7a1 by binding to the E-box (CACATG) at the 219/ 214 bp region of Cyp7a1 promoter [80]. Several oscillating nuclear receptors such as PPARα and LRH-1 are involved in circadian regulation of CYP7A1 [81]. LRH-1 acts as an activator, while PPARα acts as a suppressor [81]. Noshiro et al. report that CLOCK protein regulates the circadian expression of CYP7A1 through modulating DBP, DEC2, and REV-ERBα [81]. However, deletion of Dbp, Dec2, or Rev-erbα does not abolish circadian expression of CYP7A1, indicating that other mechanisms are involved in rhythmic expression of CYP7A1. Zhang et al. and Duez et al. found that REV-ERBα is essential for the circadian expression of CYP7A1 [24, 25]. Mechanistic studies reveal that REV-ERBα regulates CYP7A1 through repression of LRH-1, SHP, and E4BP4 [24, 25].

4.4.9

CYP8B1

Sterol 12α-hydroxylase (CYP8B1) is a liver specific enzyme that catalyzes the synthesis of cholic acid (CA) from cholesterol and determines the ratio of CA over chenodeoxycholic acid (CDCA) in the bile [82]. Due to an important role of CA in enhancing intestinal cholesterol absorption, CYP8B1 is crucial for cholesterol homeostasis [83]. Cyp8b1 mRNA oscillates in a time-dependent manner with the lowest level at ZT10. Similarly, CYP8B1 protein shows a significant diurnal rhythm (higher expression in the late dark phase) [84]. Clock genes may regulate bile acid and cholesterol homeostasis partly through modulation of CYP8B1 expression (Table 4.4). Shp ablation causes abnormal accumulation of and increased synthesis of bile acids partly due to de-repression of CYP8B1 [59]. Clock genes RORα and RORγ enhance CYP8B1 expression and increase liver and serum cholesterol, leading to hepatic steatosis [62]. Circadian CYP8B1 expression is regulated by RORα. RORα stimulates Cyp8b1 expression and maintains its rhythm through recruiting the histone acetylase CBP and promoting histone acetylation of the Cyp8b1 promoter [26]. As a Rorα paralog, Rorγ also participates in circadian regulation of CYP8B1 expression [62]. Rorγ ablation blunts Cyp8b1 rhythm and reduces the levels of plasma and liver bile acids [81]. Clock mutation abolishes the circadian rhythm of CYP8B1 in both LD and DD conditions [81]. DEC2 represses Cyp8b1 expression by binding to the specific E-box (CACATG) in the promoter [80]. REV-ERBα inhibits human CYP8B1 transcription by binding to the RevRE element in the promoter [85]. However, hepatic CYP8B1 expression is unchanged in Rev-erbα-deficient mice, indicating that regulation of CYP8B1 by REV-ERBα is species specific [25].

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4.4.10 CYP11A1 CYP11A1, a rate-limiting enzyme in corticosterone synthesis, is regulated by E4BP4. E4bp4 ablation upregulates CYP11A1 expression, and blunts its rhythmicity in mouse intestine [27]. Mechanistic studies reveal that E4BP4 trans-represses Cyp11a1 through specific binding to a D-box in the promoter region. E4BP4 binding to the Cyp11a1 D-box exhibits a circadian rhythm in the ileum. The minimal and maximal E4BP4 binding (or recruitment), respectively, coincides with the maximal (corresponding to the highest rate of corticosterone synthesis) and minimal (corresponding to the lowest rate of corticosterone synthesis) Cyp11a1 mRNA expression [27].

4.5

Effects of CYPs on Circadian Clock

As noted above, circadian clock controls the expression of a number of CYP enzymes. In turn, CYP enzymes can have an influence on circadian clock. To be specific, CYP enzymes can affect circadian rhythms by modulating melatonin, NAPDH, and glucocorticoid levels. Melatonin regulates the sleep/wake cycle and circadian rhythms [86]. CYP enzymes such as CYP1A1, CYP1A2, CYP1B1, and CYP2C19 may influence the circadian clock activity by modulating the metabolism of melatonin [87]. CLOCK/NPAS2:BMAL1 binds to E-box sequences to regulate gene expression in the presence of reduced nicotinamide adenine dinucleotides (NADH and NADPH). However, the oxidized forms of nicotinamide adenine dinucleotides (NAD+ and NADP+) inhibit binding of CLOCK/NPAS2:BMAL1 to DNA sequences [88, 89]. Therefore, the ratio of NAD(P)H over NAD(P)+ dictates the binding of CLOCK/NPAS2:BMAL1 to E-boxes [88, 89]. It is well known that NADPH as a cofactor is consumed in CYP-mediated reactions. There is possibility that CYP activities affect the binding of CLOCK/NPAS2:BMAL1 to promoter sequences and alter their transcriptional activities. CYP11A1, CYP11B1, and CYP11B2 play a vital role in glucocorticoid synthesis [90]. Since glucocorticoids exhibit circadian oscillations and drive circadian rhythms, impaired functions of these three CYP enzymes may lead to loss of glucocorticoid rhythmicity and to disrupted circadian rhythms [91].

4.6

Concluding Remarks

A number of CYP enzymes display circadian rhythms in their expression and activities, accounting for dosing time-dependent drug efficacy and/or toxicity. Regulation of rhythmic CYPs by the circadian clock system is mainly achieved through the clock genes (including Bmal1, Clock, Npas2, Rev-erbα, Dbp, E4bp4, and Rorα/

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γ) and clock-controlled transcription factors (e.g., DEC2, PPARα/γ, LRH-1, and HNF1α). On the other hand, CYP enzymes can regulate melatonin, glucocorticoid, and NAPDH levels which are associated with circadian clock function, suggesting intricate relationships between the circadian clock and CYP enzymes. The authors propose that circadian CYP metabolism should be considered in chronotherapeutics to optimize drug efficacy and reduce adverse effects.

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Chapter 5

Circadian Clock and Non-CYP Phase I Metabolism Min Chen, Tianpeng Zhang, Danyi Lu, and Baojian Wu

Abstract Circadian rhythms in drug metabolism by non-CYP phase I enzymes (i.e., MAOs) have been recognized since 1970s. The profound effects of the circadian clock on non-CYP phase I metabolism are highlighted recently in mice lacking the clock gene Bmal1, E4bp4, or Rev-erbα. Clock-deficient mice show altered expression of non-CYP phase I enzymes and blunted rhythms in enzyme expression. In addition, circadian expressions of non-CYP phase I enzymes (e.g., FMO5) are associated with time-varying drug metabolism, potentially resulting in chronotoxicity and chronoefficacy. Circadian drug metabolism may be exploited in dosing regimen optimization to maximize efficacy and reduce toxicity. In this chapter, we review non-CYP phase I enzymes whose expression and activity vary with time of the day. We also discuss the molecular mechanisms underlying circadian expression of non-CYP phase I enzymes. Keywords Circadian clock · Non-CYP phase I enzymes · Drug metabolism · Chronopharmacokinetics

5.1

Introduction

Metabolism generally facilitates elimination of drugs from the body, and is thus normally considered to be a detoxifying process [1]. Although CYP enzymes account for majority of phase I metabolic reactions, non-CYP phase I enzymes also play an important role. The non-CYP phase I enzymes involved in drug metabolism are flavin-containing monooxygenases (FMOs), molybdenum hydroxylases [aldehyde oxidase (AO) and xanthine oxidase (XO)], carboxylesterase (CES), monoamine (MAO), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH) [2]. M. Chen · T. Zhang · D. Lu · B. Wu (*) Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_5

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Circadian rhythm in drug metabolism by a non-CYP phase I enzyme (i.e., MAOs) was first reported in the 1970s [3]. The profound effects of the circadian clock on non-CYP phase I metabolism were highlighted recently in mice lacking the clock gene E4bp4 (E4-binding protein 4). E4bp4 ablation reduces CES2-mediated metabolism of CPT-11 (irinotecan, a first-line drug for treating colorectal cancer) thus increases the system exposure of CPT-11 in mice [4]. In addition, circadian expression of a non-CYP phase I enzyme (e.g., FMO5) is associated with time-varying drug metabolism, potentially resulting in chronotoxicity and chronoefficacy [5]. Therefore, circadian drug metabolism may be exploited in dosing regimen optimization to maximize efficacy and reduce toxicity. In this chapter, we review non-CYP phase I enzymes whose expression and activity vary with time of the day. We also discuss the molecular mechanisms underlying circadian expression of non-CYP phase I enzymes.

5.2

Mammalian Circadian Clock System

Circadian clocks are present in virtually all light-sensitive organisms, including cyanobacteria, fungi, plants, protozoans, and metazoans [6]. The main function of these time-keeping devices is to adapt the physiological functions of the organisms to the diurnal changes of the external environment in an anticipatory way [7]. In mammals, many physiological and behavioral processes are subjected to circadian rhythms, for instance, the heartbeats, blood pressure, body temperature, sleep-wake cycle, and liver metabolism [8]. Circadian rhythms are driven by a central clock that resides within the suprachiasmatic nuclei (SCN) of the hypothalamus [8]. The SCN perceives light information that is projected via the retinohypothalamic tract. This information is then converted into neurotransmitter signals (e.g., glutamate), which induce the circadian expression of clock genes, such as PER1 and PER2 [9]. Through multiple output pathways, the SCN synchronizes peripheral clocks existed in peripheral tissues (e.g., liver, kidney, and the digestive tract) [10]. At the molecular level, circadian clock system is composed of three interconnected autoregulatory feedback loops [6, 11]. The main oscillators of core loop are BMAL1 (brain and muscle Arnt-like protein-1), CLOCK (circadian locomotor output cycles kaput), PER (period), and CRY (cryptochrome). Transcription of PER and CRY are activated by the BMAL1/CLOCK heterodimer via binding to E-box elements in their promoters, resulting in cytoplasmic accumulation and heterodimerization of PER and CRY. This heterodimer can enter the nucleus to inhibit the transcriptional activation driven by BMAL1/CLOCK in a negative feedback fashion. Once PER and CRY are phosphorylated and degraded, their inhibition effects are no longer available and a new cycle of transcription-translation can start [12]. The second loop complements the core feedback loop, in which CLOCK/BMAL1 heterodimer activates transcription of REV-ERBα/β (negative regulators) and retinoic acid related orphan receptor α/β/γ (RORα/β/γ, positive regulators). These nuclear receptors compete for binding to the RevRE (or RORE)

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elements in the promoters of target genes (e.g., BMAL1 and E4BP4) to regulate gene expression [13]. The third loop is made up of transcription factors DBP (albumin D site-binding protein) and E4BP4, which synergistically regulate expression of genes including PER via acting on D-box elements in promoter region. DBP induces, whereas E4BP4 inhibits transcription of target genes [13]. Through these feedback loops, the circadian homeostasis in various cells and tissues can be properly maintained even under constant environmental conditions [13].

5.3 5.3.1

Mammalian Non-CYP Phase I Enzymes and Their Functions FMOs

FMOs (EC 1.14.13.8) are a class of nicotinamide-adenine dinucleotide phosphate (NADPH)- and oxygen-dependent microsomal FAD-containing enzymes that function as sulfur, nitrogen, and phosphorus oxygenases [14]. There are five functional FMO genes in humans, namely FMO1, FMO2, FMO3, FMO4, and FMO5 [15]. FMO1–4 are clustered in the region q24.3 on chromosome 1, whereas FMO5 is located at 1q21.1 [14]. The chromosome 1 also contains six pseudogenes, designated FMO6P-FMO11P, which are incapable of producing a correctly spliced mRNA [16]. There are the same number of functional Fmo genes in mice. Fmo1–4 are clustered on chromosome 1 and Fmo5 is located on chromosome 3 [15]. Fmo6, Fmo9, Fmo12, and Fmo13 are four Fmo pseudogenes in mice [15]. FMOs are present in major sites of drug metabolism, such as liver, kidney, small intestine, and lung [17]. However, there are marked tissue differences in expression of FMO enzymes. FMO3 and FMO5 are mainly expressed in human liver. FMO1 and FMO2 are highly expressed in human kidney. By contrast, FMO2 is abundantly expressed in human lung [18]. There are also tissue differences in expression of FMO enzymes in mice. FMO1 is highly expressed in mouse kidney. FMO2 is mainly present in mouse lung, and FMO5 is primarily expressed in mouse liver [17]. Additionally, significant gender differences in expression of FMOs are observed in mice. For example, FMO3 is present in female mouse liver, but is absent in male mouse liver [17]. The catalytic mechanism of FMOs has been established in previous studies [19– 21]. For catalysis, FMOs require NADPH as a cofactor, FAD as a prosthetic group, and molecular oxygen as a cosubstrate [22]. The steps of catalytic mechanism are as follows: (1) FAD undergoes 2-electron reduction by NADPH; (2) The reduced flavin FADH2 reacts rapidly with O2 to produce a stable C4a-hydroperoxyflavin (FAD-OOH); (3) FAD-OOH reacts with a soft nucleophile, resulting in 1 atom of molecular oxygen being transferred to the substrate and 1 atom to form water; (4) The final step in the cycle is the release of H2O and then release of NADP+ (Fig. 5.1). FMO enzymes are active in the C4a-hydroperoxyflavin form in the

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Fig. 5.1 Catalytic cycle of FMOs

catalytic reaction. The C4a-hydroperoxyflavin intermediate is capable of oxygenating any soft nucleophile that is accessible to the active site (Fig. 5.1) [20]. This unusual catalytic mechanism of FMOs leads to their broad substrate specificity [23]. Many compounds containing a soft nucleophile are substrates of FMOs, for instance, nitrogen-containing (e.g., trimethylamine and trifluoperazine) and sulfurcontaining compounds (e.g., thiourea and sulindac sulfide) [19, 22].

5.3.2

AOs and XOs

Molybdenum hydroxylases include AO (EC 1.2.3.1) and XO (EC 1.17.3.2)/xanthine dehydrogenase (EC 1.17.1.4). XO and xanthine dehydrogenase are two interconvertible forms of the same enzyme, known as xanthine oxidoreductase [24]. These enzymes generally contain 2Fe/2S N-terminal domain, Mo-containing C-terminal domain (substrate binding site), and flavin-containing region [24]. AO and XO are structurally similar, however, their biochemical and physiological function are different. AO is involved in adipocytic differentiation and metabolism of endogenous substrates such as trans-retinaldehyde and pyridoxal [25–27]. By contrast, physiological functions of XO are more complex. XO participates in a variety of biochemical reactions, including the oxidative hydroxylation of hypoxanthine to xanthine and the subsequent conversion of xanthine to uric acid [28]. Additionally, XO also plays an important role in vascular injuries, inflammatory diseases, and chronic heart failure [29, 30]. Molybdenum hydroxylases are distributed in many tissues including liver, lung, kidney, and small intestine [31]. However, there are major differences in tissue distribution between AO and XO. In mammals, higher XO expression is found in liver, proximal intestine, and lactating mammary gland, whereas AO is more abundantly expressed in the liver, kidney, lung, and brain [32]. By contrast, AO level is very low in the intestine, and AO transcript is absent in mammary gland [32].

5 Circadian Clock and Non-CYP Phase I Metabolism Fig. 5.2 Intra-molecular electron transport system of molybdenum hydroxylases. Arrows indicate the direction of electron flow [34]

93 Electron donor

Mo+6

Mo+4

FAD

Fe-S

O2, NAD+

Cytochrome c

Molybdenum hydroxylases catalyze both oxidation and reduction reactions. Molybdenum hydroxylases-mediated oxidation reactions appear to play a more important role in xenobiotic metabolism [33]. Oxidation reaction catalyzed by molybdenum hydroxylases is essentially a process of electron transport (Fig. 5.2) [33, 35, 36]. First, a substrate (an electron donor, e.g., xanthine) acts on the molybdenum site, reducing Mo from the oxidation state of +6 to +4. Second, reducing equivalents transfer directly to the FAD site or indirectly via the ironsulfur (Fe-S) center, and the enzyme is reoxidized by interaction with oxygen. Finally, an oxygen atom from water (the ultimate source of the oxygen atom) binds to the electron donor which lost electrons [34]. Based on this mechanism, AOs and XOs are capable of catalyzing nucleophilic oxidation at an electrondeficient carbon atom which often times is adjacent to a ring nitrogen atom in N-heterocycles (e.g., purines, pyrimidines, pteridines, and quinolines) [37].

5.3.3

CES

CES (EC 3.1.1.1) are a α,β-serine hydrolase multigene family of mammalian enzymes, which catalyze the hydrolysis of esters, amides, thioesters and carbamates [38, 39]. CES hydrolyze their substrates using a two-step catalytic mechanism. In the first step, the base-activated serine oxygen atom attacks the carbonyl carbon of an ester, amide, or thioester substrate, resulting in formation of an acyl-enzyme intermediate and the liberation of an alcohol, amine, or thiol metabolite. In the second step, cleavage of the acyl-enzyme intermediate by a water molecule generates a carboxylic acid product [40]. The products of hydrolysis are generally more polar than the parent compound [40]. This property aids in the elimination of xenobiotics (e.g., esters) that might be potentially harmful to the body. In mammals, CES have been classified into five families based on amino acid homology, designated as CES1-CES5 [41]. Each human CES family contains one member only, whereas mouse Ces family contains one or multiple members. For example, mouse Ces1 family consists of eight members (i.e., Ces1a, Ces1b, Ces1c, Ces1d, Ces1e, Ces1f, Ces1g, and Ces1h) [41]. Enzymes from CES1 and CES2 families are main contributors to drug metabolism [41]. CES share overlapping substrate specificity, however, the enzymes may show a metabolic preference over

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certain groups of drug substrates [38]. For instance, the CES1 enzyme hydrolyzes the compounds with a bulky acyl group and a small alcohol group, whereas CES2 prefers substrates with a small acyl group and a large alcohol group [42, 43]. The CES enzymes are expressed in multiple tissues including the liver, small intestine, kidney, and lung [44]. However, there are marked tissue differences in expression of CES enzymes. In humans, both CES1 and CES2 are expressed in the liver, but CES1 expression is much higher than CES2. By contrast, only CES2 is present and highly expressed in the intestine. The selective expression of CES2 in the intestine may represent a defensive barrier due to its role in hydrolyzing harmful xenobiotics [45]. However, this selective expression may also significantly affect the disposition of certain xenobiotics after oral administration. For example, the CES substrates such as O-isovaleryl-propranolol undergo extensive first-pass hydrolysis in the small intestine [45, 46].

5.3.4

ADHs and ALDHs

ADHs (EC 1.1.1.1) are a family of NAD+/NADH-dependent isozymes that catalyze the oxidation of alcohols to their corresponding aldehydes. Mammalian ADHs exhibit different molecular forms which are grouped into classes 1–6 [47]. ADH1 is abundant in the liver and primarily involved in the metabolism of ethanol. ADH1 family contains three subfamilies, namely ADH1A, ADH1B, and ADH1C. ADH1B subfamily consists of ADH1B1, ADH1B2, and ADH1B3, whereas ADH1C consists of ADH1C1 and ADH1C2 [48]. ADH4 is mainly expressed in stomach mucosa and other epithelia, and it participates in catalyzing alcohols and retinoids [48]. ADH3 is expressed in most tissues but plays a minor role in metabolizing alcohols [49]. ADH2 and ADH5 are poorly studied, and little is known about their substrates and characteristics [2]. ALDHs (EC 1.2.1.3) are a group of NAD(P)+-dependent enzymes involved in the metabolism of a wide variety of aliphatic and aromatic aldehydes [50]. Human ALDH family contains 19 functional genes and three pseudogenes [51]. The 19 functional genes are classified into 11 families and 4 subfamilies based on amino acid sequence similarity [51]. ALDH1 and 2 families play a primary role in xenobiotic metabolism. The ALDH1 family contains six functional genes: ALDH1A1, 1B1, 1A2, 1A3, 1L1, and 1L2. Of note, ALDH1A1 and 1B1 are involved in acetaldehyde metabolism [51, 52]. The ALDH2 family with only member is critical in ethanol metabolism [51].

5.3.5

MAOs

MAOs (EC 1.4.3.4) are mammalian flavoenzymes bound to the outer mitochondrial membrane. The two MAO isoenzymes MAO-A and MAO-B share ~70% sequence

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identity [53]. Their amine oxidase domain is homologous to that of the water-soluble polyamine oxidases and flavin-dependent histone demethylases [53]. MAOs are present in all human tissues except red cells, but some human tissues express only one form of MAO [54]. For example, MAO-A is uniquely expressed in human placental mitochondria, while MAO-B is uniquely expressed in human platelet mitochondria [54]. MAOs primarily oxidize primary, secondary, and tertiary amines. The substrates are catalyzed by MAOs to form an imine which is then hydrolyzed to the end product, an aldehyde [55]. The aldehydes formed are usually further oxidized by ALDHs or AOs to their corresponding carboxylic acids or by the aldehyde reductases to the alcohols [55]. MAOs-mediated reaction is not NADPH-dependent, but it does require oxygen for regeneration of the oxidized enzyme [55]. Additionally, MAOs play an important role in the metabolism of neurotransmitters such as dopamine, serotonin, and norepinephrine (NE) [56–58]. Intriguingly, MAOs inhibitors have been developed to treat neurodegenerative diseases [59].

5.4 5.4.1

Role of Non-CYP Enzymes in Drug Metabolism FMOs and Drug Metabolism

FMOs are one class of the most important non-CYP phase I enzymes involved in drug metabolism [60]. FMO1 and FMO3 have a broad substrate specificity [22]. They share some overlapping substrates such as benzydamine, itopride, and tamoxifen, but also show distinct substrate selectivity. For example, several drugs (e.g., chlorpromazine, imipramine, and quazepam) are specific substrates of FMO1, while procainamide is exclusively metabolized by FMO3 [22]. By contrast, very few drugs are metabolized by FMO2, for example, ethionamide, methimazole, and thiacetazone [61–63]. FMO5 has a limited number of drug substrates, and it generally catalyzes Baeyer–Villiger oxidation reactions [64]. FMO4 is marginally expressed in mammals. So far, little is known about the substrate specificity of FMO4 and its role in drug metabolism may be negligible [22]. In addition to tertiary amines, FMOs also catalyze metabolism of primary and secondary amines, generating N-oxides [14]. In general, FMO-mediated metabolism reactions represent a detoxification pathway. For example, N-deacetyl ketoconazole (the primary metabolite of ketoconazole, a secondary amine) is N-oxygenated sequentially by FMOs to form an N- hydroxylamine and further to a nitrone. Although N-deacetyl-ketoconazole is formed in the liver and is more cytotoxic than ketoconazole [65, 66], its N-oxide metabolite is a polar compound and readily excreted from the body. Sulfides are another type of FMO substrates. They are S-oxygenated by FMOs to the sulfoxides, which usually are toxic to the body. Thiourea S-oxygenation is an example of FMO-dependent metabolism reactions, and is thought to be an important mechanism of thiourea toxicity in mammals [67]. FMOs can S-oxygenate thioureas

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to sulfine that can be further converted to the reactive sulfinic acid. Sulfenic acids not only can reversibly react with GSH and drive oxidative stress through a redox cycle, but also can react with other sulfhydryls including cysteine residues in various proteins and therefore cause protein denaturation [67]. Additionally, thiobenzamide is a potential liver toxicant that may result from FMO-mediated S-oxygenation [67]. FMO5 displays no or poor metabolic activity toward classical FMO substrates, and is known to catalyze the N- or S-oxygenation of a small number of drugs such as nomifensine (N-oxygenation) and ranitidine (S-oxygenation) [68, 69]. Recently, FMO5 has been identified as a Baeyer–Villiger monooxygenase. It is able to catalyze oxidation of a broad range of carbonyl compounds through insertion of an oxygen atom into a carbon–carbon bond adjacent to the carbonyl group (aldehyde or ketone) [70]. FMO5 metabolizes several drugs and metabolites including pentoxifylline (PTX), nabumetone, E7016, and S-methyl-esonarimod (an active metabolite of the anti-rheumatic esonarimod) via Baeyer–Villiger reactions [5].

5.4.2

AOs/XOs and Drug Metabolism

As the name implies, AOs are known to primarily catalyze the oxidation of aldehydes to carboxylic acids, for example, vanillin, an aromatic aldehyde, is rapidly converted to vanillic acid by AOs [37]. In addition to aldehydes as parent compounds, aldehyde intermediates formed during drug metabolism can be catalyzed by AOs. Citalopram and tamoxifen are two examples that illustrate the role of AOs in the oxidation of aldehyde intermediates. Citalopram, an antidepressant drug, is primarily catalyzed by MAO to an aldehyde intermediate which is subsequently oxidized to the citalopram propionic acid metabolite by AOs [71]. Similarly, tamoxifen, a nonsteroidal antiestrogen, is deaminated by MAO to the corresponding aldehyde intermediate which is further oxidized to the oxyacetic acid metabolite [72]. Aldehyde products generated via CYP-mediated metabolism of drugs (e.g., tolbutamide and cyclophosphamide) are also subjected to oxidation by AOs [73, 74]. AOs catalyze the oxidation of iminium ion intermediates which are formed during the metabolism of alicyclic amines (e.g., pyrrolidine, piperidine, piperazine, or morpholine) to their corresponding lactam metabolites [75]. In this type of reactions, amine (e.g., nicotine) is firstly converted to an iminium ion intermediate through CYPs or MAOs, and then hydrated by AOs to the corresponding lactam metabolite (e.g., cotinine) [76]. Lactam metabolites can be generated from wellknown drugs such as tremorine [77], prolintane [78], momelotinib [79], and phencyclidine [80]. AOs also metabolize drugs containing heteroaromatic rings [81]. N0 -methylnicotinamide, an endogenous substrate, is converted to N0 -methyl-2pyridone-5-carboxamide and N0 -methyl-4-pyridone-3-carboxamide by AOs [75, 81]. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase-∂, is primarily metabolized by AOs to GS-563117 [82]. Lenvatinib, an orally available multityrosine kinase inhibitor, is partially metabolized by AOs [83]. Other drugs/

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metabolites that are metabolized by AOs include zaleplon (catalyzed by CYP3A4 to N-desethylzaleplon and subsequently by AOs to the corresponding 5-oxozaleplon) and methotrexate (its metabolite 7-hydroxymethotrexate is primarily metabolized by AOs) [84, 85].

5.4.3

CES and Drug Metabolism

Many environmental toxicants and therapeutics are esterified compounds (reviewed in [86]). Examples include pyrethroid insecticides, phthalate esters, and narcotics (e.g., cocaine and heroin). These compounds are cleared from the body in part by the actions of CES. Besides esters, thioesters, amides, and carbamates are all potential substrates of CES. Cardiovascular drugs, including the angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (ARBs), anticoagulants, statins, and fibric acids, are CES substrates. All ACEIs except captopril and lisinopril are ester prodrugs that are hydrolyzed by human CES1 to their corresponding therapeutically active carboxylic acids [38]. Candesartan cilexetil, olmesartan medoxomil, and azilsartan medoxomil are three prodrugs belonging to ARBs, which are catalyzed by human CES2 in the small intestine to form an active metabolite [87, 88]. The three anticoagulants aspirin, clopidogrel, and prasugrel are subjected to CES hydrolysis. It is noted that hydrolysis by human CES2 can be either an inactivation or activation pathway for aspirin depending on the pharmacological activity [89]. The parent compound aspirin is an antiplatelet agent, and its metabolite salicylate is an anti-inflammatory agent. CES2 hydrolysis represents an inactivation pathway for the antiplatelet effect, but an activation pathway for anti-inflammatory activity [38, 89]. Additionally, lipid-lowering agents are human CES1 substrates, including fibric acids (e.g., clofibrate and fenofibrate) and two thiolactone statins (e.g., lovastatin and simvastatin) [38]. Some CNS stimulants, opiate agonists, and anti-convulsants are CES substrates. For example, cocaine, a CNS stimulant, is hydrolyzed by both human CES1 and CES2 at two separate ester sites. Human CES1 catalyzes the hydrolysis of the methyl ester to produce benzoylecgonine, whereas CES2 catalyzes the hydrolysis of the benzoyl ester to produce ecgonine methyl ester [90]. The opiate agonist meperidine is hydrolyzed by human CES1 to meperidinic acid, an inactive metabolite [91]. The anti-convulsant rufinamide is primarily catalyzed by human CES1 to its carboxylic acid metabolite, which is then subjected to direct renal elimination or indirect renal elimination after glucuronidation [92]. The oncology drugs irinotecan and capecitabine are two carbamates which can be hydrolyzed by CES [38]. Irinotecan is a prodrug hydrolyzed by both CES1 and CES2 to the active metabolite 7-ethyl-10-hydroxy camptothecin (SN-38) [93]. Capecitabine is a prodrug hydrolyzed by CES2 to an intermediate metabolite (50 -deoxy-5-fluorocytidine), and further metabolized by cytidine deaminase and thymidine phosphorylase to 5-fluorouracil, an anti-tumor agent [94]. Additionally,

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mycophenolate, an immunosuppressant drug, is hydrolyzed by CES1 to form the active metabolite mycophenolic acid [95]. These findings highlight the importance of the CES hydrolysis in drug metabolism and detoxification.

5.4.4

ADHs/ALDHs and Drug Metabolism

In addition to ethanol, many drugs can be metabolized by ADHs [96–99]. For example, ethambutol and its L-isomer are metabolized by liver ADHs to form an aldehyde (oxidative) product [96]. Hydroxyzine is primarily metabolized by human ADHs to the metabolite cetirizine, an anti-allergic agent [97]. Celecoxib is probably metabolized by ADH1 and ADH2 [98]. The reverse transcriptase inhibitor abacavir is oxidized by ADHs to form a carboxylic acid [99]. Additionally, ADHs can act on hydroxylated metabolites of CYP enzymes [2]. For example, tolbutamide is firstly metabolized by CYP2C9 to hydroxytolbutamide, and then oxidized by ADHs to carboxytolbutamide. Terfenadine is mainly metabolized by CYP3A4 to terfenadine alcohol, which is further oxidized by both CYP3A4 and ADHs to form the active carboxylic acid metabolite fexofenadine [100, 101]. Similarly, ebastine undergoes hydroxylation and subsequent oxidation by ADHs to form the active metabolite carebastine [102]. ALDHs play a role in metabolism of a few drugs (e.g., hydroxyzine and ethambutol) [96, 97]. Oxidation of aldehydes is generally considered as a detoxification process, however, it can cause toxicity in some cases. For example, ALDHs are involved in the metabolism of cyclophosphamide (CP), an alkylating agent frequently used to treat several malignant and nonmalignant hematologic diseases. CP is a prodrug that requires activation by several hepatic CYPs (e.g., CYP2B6, CYP2C9, and CYP3A4) to the active metabolite 4-hydroxycyclophosphamide (4-HCP) [103]. 4-HCP is further oxidized by ADHs or ALDHs (i.e., ALDH1A1, ALDH3A1, and ALDH5A1) to produce phosphoramide mustard and acrolein [104, 105]. These metabolites ultimately alkylate DNA, resulting in inhibition of DNA synthesis and cell death [104, 105].

5.4.5

MAOs and Drug Metabolism

MAOs catalyze the oxidation of structurally diverse amines, including endogenous neurotransmitters (e.g., dopamine, noradrenaline, serotonin, tyramine, and 2-phenylethylamine), histamine receptor antagonists (e.g., diphenhydramine and betahistine), adrenoceptor ligands (e.g., phenylephrine and propranolol), and selective serotonin re-uptake inhibitors (e.g., sertraline and citalopram) [106–109]. Of note, neurotransmitters are the most well-characterized MAO substrates [110]. These substrates are closely associated with depression and neurodegenerative diseases [111]. For instance, dopamine is metabolized by MAOs to form

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3,4-dihydroxyphenylacetaldehyde, a toxic and reactive intermediate that potentially serves as a “chemical trigger” in the pathogenesis of Parkinson’s disease [112].

5.5

Diurnal Expression of Non-CYP Phase I Enzymes

Identifying circadian drug-processing genes is essential for a better understanding of chronopharmacokinetics and of chronopharmacology. In recent years, a number of non-CYP phase I enzymes have been shown to exhibit diurnal variations. Their rhythmic expression may account for time-varying metabolism and pharmacokinetics. Here, we summarize non-CYP phase I enzymes showing diurnally rhythmic expression.

5.5.1

Circadian Rhythm in FMO Expression

Williams first reported the rhythmic expression of FMO in rabbits [113]. Rabbit FMO activity exhibits a diurnal rhythm in the lung with a two-fold variability (the highest level at 12:00 AM and the lowest level at 20:00 PM). The investigators also determined FMO activity in rabbit liver using the substrate N,N-diemethylaniline (DMA), but found no temporal variations in hepatic FMO activity [113]. However, this study may not exclude the possibility of rhythmic feature of FMOs in the liver because DMA is a poor substrate of certain FMOs such as FMO5 (with high expression in the liver) thus metabolism of DMA cannot represent the activity of all FMO enzymes [68, 69]. In fact, a recent study demonstrates hepatic Fmo5 as a circadian gene whose expression oscillates according to time of the day (see the following paragraph). Chen et al. characterized temporal expression of hepatic FMO5 in mice [5]. FMO5 mRNA and protein show robust diurnal rhythms with peak values at zeitgeber time (ZT) 10/14 [lights on at 7:00 AM (¼ZT0) and lights off at 19:00 PM (¼ZT12)] and trough values at ZT2/22 in mouse liver (Fig. 5.3) [5]. Consistently, a diurnal rhythm is observed for in vitro microsomal Baeyer–Villiger oxidation of pentoxifylline (PTX), a specific reaction catalyzed by FMO5. Pharmacokinetic studies reveal a more extensive Baeyer–Villiger oxidation of PTX at dosing time of ZT14 than at ZT2, consistent with the diurnal pattern of FMO5 protein (Fig. 5.3) [5]. However, the pharmacokinetic behavior of PTX is dosing time-independent although slight differences in plasma/liver concentrations are observed (Fig. 5.3). This was probably because PTX-M (PTX metabolite) formation by FMO5 was a non-major metabolic pathway for PTX as CYP enzymes make a significant contribution [5]. Alterations in a non-major metabolic pathway may not cause sufficient changes in total parent drug metabolism and pharmacokinetics. We investigate temporal expression of hepatic FMO3 in mice. Fmo3 mRNA displays a robust diurnal rhythm with a maximum value at ZT14 and minimum value

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Plasma/liver PTX-M levels ZT2 ZT14

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Fig. 5.3 Diurnal expression of hepatic FMO5 in mice. Time-varying metabolic activity of FMO5 substrates was positively correlated with temporal expression of FMO5

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Fig. 5.4 Diurnal expression of hepatic FMO3 in mice

at ZT2 (Fig. 5.4; unpublished data). FMO3 protein also shows a diurnal rhythm with a two-fold variability and a peak value at ZT18. This suggests mouse Fmo3 as a circadian gene (Fig. 5.4). The rhythmic expression of FMO3 may lead to timevarying pharmacokinetics of its substrates such as procainamide [22]. However, whether this is true or not awaits further investigations.

5.5.2

Circadian Rhythm in AO and XO Expression

Beedham et al. first reported circadian rhythms in the activities of molybdenum hydroxylases in guinea pigs [114]. The activities of AOs and XOs peak during the later light and early dark phases (from 12:00 AM to 18:00 PM) [114]. Circadian variations in the activities of AOs and XOs are also observed in rats (the maximum

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activities occur at 15:00 PM) [115]. Likewise, mouse molybdenum hydroxylases display diurnal rhythms [116]. However, mouse AOs and XOs peak at the night phase [116]. Terao et al. revealed mouse Ao1 and Ao4 as circadian genes [117]. Mouse Ao1 mRNA exhibits a marked circadian rhythm with a peak value at ZT10 and a trough value at ZT22 (a four-fold difference between ZT10 and ZT22) [117]. By contrast, Ao4 displays a diurnal oscillation in mouse liver with a peak value at the night phase (e.g., ZT16) and a trough value at the light phase (e.g., ZT4) [117]. Interestingly, Ao4 ablation down-regulates expression of multiple circadian clock genes (e.g., Per2, Clock, Dbp, and Rorα) in mice, suggesting its role in the control of circadian rhythms [117]. This alteration in the circadian clock system may be mediated by AO4 products (e.g., all-trans retinoic acid) or substrates [117].

5.5.3

Circadian Rhythm in CES Expression

CES play an important role in hydrolyzing ester- and amide-containing compounds. A majority of Ces transcripts displayed circadian rhythms over time (a standard 12-h light/dark cycle), with higher levels in the dark phase [118]. Zhang et al. have shown significant circadian variations in mRNAs of hepatic Ces1b, 1d, 1e, 2a, and 2e, and weak daily variations in expressions of Ces1g, 1 h and 3a (peak/trough values were 1.1, 1.2, and 1.4, respectively) in mice [118]. In addition to the liver, Ces3 also oscillates in a time-dependent manner in mouse heart [119]. Recently, Zhao et al. uncover circadian time-dependent variations in four Ces2 genes (i.e., Ces2a, Ces2b, Ces2c, and Ces2e) in wild-type mice (a higher expression at ZT12 than at ZT0) [4]. Consistent with the mRNA changes, the total protein of CES2 in the liver is higher at ZT12 than at ZT0. CPT-11 (irinotecan), a well-known CES2 substrate, was used to probe the activity of CES2 enzymes in microsomal metabolism assay in the study of Zhao et al. [4]. Microsomal formation of SN-38 (the hydrolytic product) from CPT-11 is time-dependent (a higher metabolic activity at ZT12 than at ZT0). This agrees well with the diurnal expression of CES2 protein [4].

5.5.4

Circadian Rhythm in ADH/ALDH Expression

Soliman et al. reported diurnal variations in ethanol concentration in blood, brain, urine, and liver of male rats [120]. Circadian fluctuations in blood/tissue ethanol concentrations might indicate a diurnal variation in the enzymatic metabolism of ethanol [121]. One possible explanation for circadian differences in hepatic activities of ADHs/ALDHs (the major enzymes for ethanol metabolism) might be the diurnal variation in enzyme expression. In the following years, North et al. reported a circadian variation in hepatic ADH activity in mice with a peak value at 20:00 PM

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[122]. Sturtevant et al. demonstrated a circadian variation in hepatic ADH activity in rats with a peak value at 3:00 AM [123]. All these findings indicated Adhs as circadian genes. Yamazaki et al. showed circadian variations in the activities of ALDH isozymes in the subcellular fractions of mouse brain and liver [124]. In this study, the authors used acetaldehyde as a probe substrate to characterize the ALDH activity [124]. A diurnal variation was observed only in female mice and there was no significant rhythm in animals under complete darkness, indicating that the ALDH activity can be influenced by the light-dark cycle and sex hormones. Furthermore, many mouse Aldh genes (e.g., Aldh1a1, 1a2, 2, 7a1, and 9a1) in the pituitary were identified as circadian genes in the study of Hughes et al. [125]. A recent study determined the temporal mRNA expression of Aldh1a1, 1b1, 2, 3a2, 4a1, 6a1, 7a1, 8a1, and 9a1 in mouse liver [118]. Aldh mRNA levels have a tendency to be higher in the dark phase, however, the variability is less than two-fold [118]. Of these genes, Aldh 7a1 exhibits a significant circadian rhythm (peak/trough ratio of 1.9) with a peak value at 2:00 AM, whereas Aldh 1a1, 2, and 3a2 display mild rhythms with a peak value at 18:00 PM [118]. By contrast, Aldh1b1, 4a1, 6a1, 8a1, and 9a1 are non-circadian genes.

5.5.5

Circadian Rhythm in MAO Expression

Chevillard et al. reported that both MAO-A and MAO-B in certain areas of the brain stem (e.g., in the areas A1, A2, and in the locus coeruleus) display significant diurnal variations in their activities in male rats maintained on a 12-h light/12-h dark schedule [126]. In this study, NE and serotonin were selected to probe MAO-A activity, while β-phenylethylamine was used to probe MAO-B activity [126]. The authors revealed robust diurnal rhythms in MAO-A/B activities with peak values during the later light phase and the early night phase and trough values at the light phase [126]. Additionally, a number of studies demonstrated that NE and dopamine levels oscillate in a time-dependent manner in various parts of mammalian brain [127–129]. The circadian variation in the levels of catecholamines in the brain stem may be accounted for by the rhythmic expression of MAOs. Mao-A mRNA exhibits a diurnal oscillation in wild-type mice with a peak value at ZT6 and a trough value at ZT24. By contrast, Mao-B expression exhibits a milder rhythm with the highest expression at ZT18 [130]. In the study of Hampp et al., the mMao-A-luciferase reporter construct was transfected into NG108-15 neuroblastoma cells and the luciferase activity was analyzed over 4 days by using real-time bioluminescence monitoring [130]. The authors observed an ~24 h oscillation in the luciferase activity whose pattern is similar to that of Dbp, a known circadian oscillator [130]. This is a strong evidence that mMao-A is a circadian gene.

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Regulation of Non-CYP Phase I Enzymes by Circadian Clock

BMAL1, E4BP4, and REV-ERBα are respective representative cis-acting proteins for E-box, D-box, and RevRE in circadian clock system. Chen et al. investigated the roles of the three cis-elements in generation of rhythmic FMO5 expression using Bmal1/, E4bp4/, and Rev-erbα/ mice [5]. FMO5 expression is downregulated and its rhythm is blunted in Bmal1/ and Rev-erbα/ mice. Positive regulation of FMO5 by Bmal1 and Rev-erbα is confirmed in primary mouse hepatocytes and/or Hepa1–6 cells. Furthermore, FMO5 expression is upregulated and its rhythm is attenuated in E4bp4/ mice. Negative regulation of FMO5 by E4BP4 has been validated using primary mouse hepatocytes. Combined luciferase reporter and chromatin immunoprecipitation assays demonstrated that BMAL1 (a known Rev-erbα activator) activates Fmo5 transcription via direct binding to an E-box (1822/1816 bp) in the promoter, whereas E4BP4 (a known Rev-erbα target gene) inhibits Fmo5 transcription by binding to two D-boxes (1726/1718 and 804/796 bp) [5]. It is concluded that circadian clock genes control diurnal expression of FMO5 through transcriptional actions on E-box and D-box cis-elements (Fig. 5.5) [5]. Rev-erbα ablation down-regulates FMO3 mRNA and protein, and blunts its rhythm in mouse liver (Fig. 5.6), suggesting that REV-ERBα positively regulates rhythmic FMO3 expression. Similar to mouse Fmo5, Fmo3 promoter presents one

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Fig. 5.5 Schematic diagrams illustrating the molecular mechanisms for generation of rhythmic non-CYP phase I enzymes. Dashed arrows denote the regulatory pathways. D: direct regulatory pathways; I: indirect regulatory pathway; U: unknown regulatory mechanisms

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potential E-box and two D-boxes, but no RevRE element [5]. Thus, the rhythmic expression of FMO3 may be directly regulated by E-box- and D-box-binding proteins and indirectly regulated by REV-ERBα. It is noted that E-box and D-box ciselements are present in mouse Fmo1 and Fmo2 promoters [5]. Therefore, it is possible that Fmo1 and Fmo2 are also circadian genes that are regulated by E-box and D-box binding proteins. Zhao et al. investigated a potential role of E4BP4 in regulation of CES and CPT-11 (irinotecan, a CES substrate) pharmacokinetics in mice [4]. Hepatic expression of CES2 oscillates in a time-dependent manner in wild-type mice. However, CES2 expression and activity in the liver are downregulated, and its timedependency is attenuated in E4bp4/ mice [4]. Since E4bp4 is a transcriptional repressor, the authors argued that a “repressor” mediator is required for positive regulation of Ces genes by E4bp4 [4]. By using a combination of luciferase reporter and EMSA assays, it has been demonstrated that REV-ERBα represses Ces2b through a direct action on a RevRE element (i.e., the 767/754 bp region) in gene promoter [4]. Furthermore, the inhibitory effects of E4BP4 on CES2B are attenuated in Rev-erbα-deficient cells [4]. The authors therefore proposed that E4BP4 regulates CES enzymes through repression of REV-ERBα (Fig. 5.5) [4]. Four nuclear receptors [i.e., constitutive androstane receptor (Car), Hnf4α, pregnane X receptor (Pxr), and liver X receptor (Lxr)] have been shown to activate the expression of CES2 enzymes (e.g., CES2A and CES2C) [131–134], whereas two nuclear receptors [i.e., peroxisome proliferator-activated receptor alpha (Pparα) and small heterodimer partner (Shp)] inhibit the expression of CES enzymes via a direct or indirect mechanism [132, 135, 136]. Since these nuclear receptors are rhythmically expressed, there is a possibility that they may contribute to the rhythmic expression of CES enzymes [118]. It has been recognized that E4bp4 competes for the D-box to antagonize the transactivation effects of PAR bZip transcription factors (Dbp, Tef, and Hlf) on their target genes [1, 13, 137]. PAR bZip proteins trans-activate Ces3 genes in mouse kidney in the study of Gachon et al. [137]. However, Zhao et al. reported that E4BP4

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positively regulates hepatic Ces3 genes (including Ces3a and Ces3b) in mouse liver [4]. These results appear to contradict with the antagonist roles of PAR bZip proteins and E4BP4 in regulating circadian gene expression. Further studies are needed to address this contradiction. Transcription of mouse Mao-A is shown to be regulated by the clock components BMAL1, NPAS2, and PER2 (Fig. 5.5) [130]. BMAL1/NPAS2 heterodimer periodically activates Mao-A transcription through action on E-box elements in gene promoter [130]. Surprisingly, Per2, a negative regulator in circadian clock system, plays a positive role in regulating the transcription of Mao-A [130]. Per2 ablation in mice leads to decreased MAO-A expression and blunted rhythm in the mesolimbic dopaminergic system, and to increased susceptibility of mice to mood disorders (probably due to the elevated dopamine levels) [130].

5.7

Concluding Remarks

A number of non-CYP phase I enzymes, including FMOs (FMO3 and FMO5), CES (CES2B and CES3), MAOs (MAO-A and MAO-B), ADHs/ALDHs (ADHs, ALDH1, 2, 3A2, and 7A1), and AOs/XOs (AO1/4 and XOs), display circadian variations in tissue expression. The main sources of diurnal rhythms of non-CYP phase I enzymes are the circadian clock components (e.g., BMAL1, E4BP4, DBP, and REV-ERBα) that transcriptionally act on three cis-elements (i.e., E-box, D-box, and RevRE or RORE) (Fig. 5.5). This knowledge is essential for a better understanding of chronopharmacokinetics and of chronopharmacology. However, there is a serious concern about the current data. The current data of circadian metabolism were derived from animals such as rats and mice (nocturnal species), thus may be not translated to humans (diurnal species). Additionally, circadian expression of certain non-CYP phase I enzymes (e.g., ALDHs) are gender-dependent. The mechanisms underlying this gender-dependency remain to be elucidated.

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Chapter 6

Circadian Clock and Phase II Metabolism Lianxia Guo, Dong Dong, Tianpeng Zhang, and Baojian Wu

Abstract Circadian clock is an endogenous oscillator (consisting of multiple clock genes) that drives circadian rhythms. Phase II metabolism is referred to conjugation reactions through which parent compounds and certain phase I metabolites are converted to more soluble products that can be readily excreted out of the body, thereby playing an essential role in drug detoxification. There is accumulating evidence supporting regulation of phase II metabolism (or phase II enzymes) by circadian clock. This regulation leads to circadian metabolism and pharmacokinetics, and possibly to time-dependent pharmacodynamics. The main objective of this chapter is to update the current knowledge about the relationships between circadian clock and phase II metabolism. The circadian patterns of phase II enzymes are presented, and the role of clock genes in regulation of phase II enzymes are discussed. Keywords Circadian clock · Phase II metabolism · UGT · SULT · GST · NAT

6.1

Introduction

Metabolism is a biotransformation process, by which endogenous and exogenous compounds are generally converted to a less toxic form and eliminated faster from the body. Drug metabolism is classified into phase I and phase II metabolism. Phase I metabolism mainly refers to oxidation, reduction, and hydrolysis reactions [1]. Phase I metabolites can be either directly excreted to the urine for elimination or undergo

L. Guo · T. Zhang · B. Wu (*) Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China D. Dong School of Medicine, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_6

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further metabolic reactions (e.g., phase II metabolism). It is noted that certain chemicals can directly undergo phase II metabolism without phase I metabolism [2]. Phase II metabolism is a class of conjugation reactions, including glucuronidation, sulfation, glutathione conjugation, acetylation, and methylation [3]. These reactions are respectively catalyzed by UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), Nacetyltransferases (NATs), and methyltransferases (MTs) [3]. Due to the addition of a polar group (e.g., glucuronic acid, sulfonic acid, and glutathione), phase II metabolites become more hydrophilic, less active or inactive, and more excretable. Phase II metabolism is involved in metabolism and detoxification of numerous xenobiotics and endobiotics, thereby playing an essential role in drug pharmacokinetics [4]. It has long been recognized that the efficacy and toxicity of many drugs depend on the time of administration [5]. For example, aspirin significantly decreases blood pressure when administered at night but shows little efficacy when administered in early daytime [6]. The hepatotoxicity of acetaminophen is more severe during the night than during the daytime [7]. However, it is until recent years that the mechanisms for time-varying drug effects are being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes regulated by circadian clock (an endogenous oscillator, please refer to Chap. 1 for details) is a key factor determining circadian metabolism, and therefore circadian changes in pharmacokinetics and pharmacodynamics [8]. This chapter aims to update the current knowledge about the relationships between circadian clock and phase II metabolism. The circadian patterns of phase II enzymes are presented, and the role of clock genes in regulation of phase II enzymes are discussed.

6.2 6.2.1

Circadian Clock and Glucuronidation Glucuronidation and UGTs

Glucuronidation is an important phase II reaction where glucuronic acid (provided by the coenzyme UDPGA) is conjugated to the substrates that possess a nucleophilic group (e.g., hydroxyl, carboxylic, amine, thiol, and acidic carbon atoms) [3]. Glucuronidation is a critical metabolic and elimination pathway for many endogenous and exogenous substances. These substances include drugs (e.g., SN-38, mycophenolic acid, and raloxifene), toxins (e.g., benzo(a)pyrene and nitrosamine), food ingredients (e.g., flavonoids), bilirubin, cholic acid, estrogens, and steroid hormones [9]. Glucuronidation contributes to metabolism of 40–70% of all clinical drugs cleared by phase II metabolism in humans [3]. UDP-glucuronosyltransferases (UGTs) catalyze the glucuronidation reactions. Mammalian UGT gene superfamily consists of 117 members [10]. In humans, 22 genes encoding UGT enzymes have been identified [11]. These genes are divided into four families (UGT1, UGT2, UGT3, and UGT8) according to DNA sequence

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homology [11]. The members of each UGT family share at least 40% sequence homology, and the members of each subfamily share at least 60% sequence homology [12]. Of note, UGT1 and UGT2 families are chief enzymes responsible for drug glucuronidation [13]. The role of UGT3 and UGT8 families in drug metabolism is negligible [13]. Although various tissues and organs express UGT enzymes, these enzymes are mainly present in the drug-eliminating organs liver, intestine, and kidney [12]. Although sharing overlapping substrates, UGT enzymes may have distinct substrate specificity. For instance, UGT1A3, UGT1A9, and UGT2A1 are major enzymes catalyzing the glucuronidation of carboxylic acids [14]. UGT1A3 and UGT1A4 catalyze the N-glucuronidation of amines [15]. However, UGT1A1 is the specific enzyme responsible for bilirubin glucuronidation [16]. UGT1A3 is highly selective toward metabolizing carboxylic acid-containing compounds [17]. UGT1A6 preferentially conjugates complex phenols and primary amines [3]. The glucuronidation of opioids is specifically catalyzed by UGT2B7 [18]. UGTs show three unique features in their catalytic function. First, the enzymes possess broad substrate specificity. The broad substrate selectivity may be accounted for by a large active site within the enzymes [19]. For example, UGT1A1 metabolizes not only small molecule drugs (e.g., acetaminophen) but also large compounds (e.g., bilirubin, etoposide, and SN-38) [20]. Second, UGT substrates with similar chemical structures may show distinct metabolic activities. The distinct metabolic activities for structurally similar substrates suggest that UGT activity is influenced by multiple interaction forces such as hydrophobic interactions, hydrogen bonds, and electrostatic forces [21]. Third, multiple metabolites can be generated from the same substrate. For instance, morphine containing two hydroxyl groups (3-OH and 6-OH) can be metabolized to form 3-O-glucuronide and 6-O-glucuronide [22]. Quercetin is metabolized by UGT1A1 to form four glucuronide isomers [23].

6.2.2

Circadian Rhythms in UGTs

UGT1A1 is highly expressed in the liver, intestine and kidney, and plays an important role in metabolism of various exogenous and endogenous compounds. Zhang et al. first reported that the mRNA expression of hepatic Ugt1a1 increased in light phase and decreased in dark phase in mice [24]. Furthermore, Wang et al. found that the mRNA and protein expression of UGT1A1 displayed circadian variations (peaking at the light-to-dark transition) in mouse liver (Fig. 6.1a) [25]. Consistent with the protein level, the glucuronidation activities of hepatic UGT1A1 toward SN-38 and estradiol (two substrates of Ugt1a1) varied according to the time of the day (lower activities at ZT2 than at ZT14) [25] (Fig. 6.1a). In addition, the rhythmicity in the mRNA expression of UGT1A1 was found in human colon cancer Caco2 cells [26]. UGT1A1 is the only enzyme that converts bilirubin (a toxic endogenous substance) to the glucuronide forms of bilirubin, a detoxification mechanism for

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A

UGT1A9

B

bilirubin

Fig. 6.1 (a) The circadian variations in the expression and activities of hepatic UGT1A1 in mice. (b) The plasma bilirubin level displays a diurnal variation in mice

Fig. 6.2 The circadian variations in the expression and activity of hepatic UGT1A9 in mice

bilirubin [16]. The plasma bilirubin level displays a diurnal variation in mice, which decreases during the light phase and increases during the dark phase (with a nadir at the light-to-dark transition) (Fig. 6.1b) [25]. The circadian bilirubin level is antiphase to the circadian expressions of UGT1A1 (a bilirubin-detoxifying enzyme), indicating that circadian UGT1A1 accounts for temporal variations in body level of bilirubin [25]. Hepatic UGT1A9 mRNA and protein display robust diurnal rhythms in wild-type mice with peak levels at ZT6 (Fig. 6.2) [27]. Rhythmicity in Ugt1a9 expression is confirmed in synchronized Hepa-1c1c7 cells. Glucuronidation of propofol (a specific UGT1A9 substrate) is dependent on the dosing time (ZT6 > ZT18), consistent with the diurnal pattern of UGT1A9 protein (Fig. 6.2) [27]. The mRNA expressions of Ugt1a5 and Ugt2a3 also show circadian rhythms in mouse liver [24]. Ugt2a3 mRNA peaks at about CT14, whereas Ugt1a5 mRNA peaks at about CT2 [24]. There are seven members of Ugt2b subfamily in mice, namely Ugt2b1, Ugt2b5, Ugt2b34, Ugt2b35, Ugt2b36, Ugt2b37, and Ugt2b38. According to a recent report, the mRNA expressions of all Ugt2b members except Ugt2b34 in the liver of mice show circadian variations with peak values in the light phase and trough values at dark phase (Fig. 6.3) [28]. Not surprisingly, the total UGT2B protein in the liver of

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Fig. 6.3 The circadian variations in the expression and activity of hepatic UGT2B in mice

mice shows a circadian fluctuation [28]. However, the protein rhythm of UGT2B is shifted (delayed) several hours compared to the mRNA (Fig. 6.3) [28]. Glucuronidation is a main metabolic pathway for morphine (an opioid analgesic) [29]. Multiple mouse UGT enzymes including UGT2B34, UGT2B35, UGT2B36, and UGT2B37 are involved in glucuronidation of morphine, and UGT2B36 contributes the most [30]. In the study of Zhang et al., morphine was chosen as the substrate to investigate the rhythmic activity of UGT2B enzymes. According to the microsomal metabolism assays, the generation rates of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) at ZT2 (daytime) are higher than those at ZT14 (nighttime) (Fig. 6.3) [28]. Based on pharmacokinetic study, AUC (the area under the curve) values of M3G and M6G at ZT2 are significantly higher than those at ZT14 [28]. These findings clearly indicated the circadian variations in the activities of UGT2B enzymes.

6.2.3

Regulation of UGTs by Circadian Clock

Loss of Bmal1 (a core clock gene) causes reduced mRNA and protein expression of UGT1A1 as well as blunted circadian rhythm of UGT1A1 in mice [25]. This indicates a role of BMAL1 in positive regulation of UGT1A1 expression and rhythmicity. By using a series of molecular biological techniques (luciferase reporter, mobility shift, and chromatin immunoprecipitation assays), it is revealed that BMAL1 trans-activates Ugt1a1 through specific binding to the E-box in the promoter region (Fig. 6.4a) [25]. It is noteworthy that Bmal1 ablation increases plasma bilirubin levels (due to reduced expression of UGT1A1) and abolishes its circadian rhythm in mice [25]. Moreover, Bmal1 ablation sensitizes mice to bilirubin-induced hepatotoxicity [25]. These findings demonstrate a critical role of the circadian clock gene BMAL1 in circadian regulation of UGT1A1 and bilirubin detoxification. In addition, knockdown of BMAL1 results in a loss of oscillations in mRNA expression of UGT1A1 in serum-shocked Caco-2 cells [31], suggesting that human BMAL1 may regulate UGT1A1 as its counterpart does to Ugt1a1 in mice. Another core clock gene REV-ERBα (a transcriptional suppressor) has been shown to regulate rhythmic expression of Ugt1a9 in mice. Loss of Rev-erbα downregulates the mRNA and protein expression of UGT1A9 and blunts their rhythms in mouse liver [27]. Glucuronidation of propofol (a substrate of

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Peaking time

A mRNA

BMAL1 Promoter

E-box

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B

Peaking time

REV-ERBα mRNA

DEC2 Promoter

E-box

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Fig. 6.4 (a) BMAL1 trans-activates Ugt1a1 through specific binding to the E-box in the promoter region. (b) REV-ERBα generates and regulates rhythmic Ugt1a9 through periodical inhibition of DEC2

UGT1A9) is reduced and its dosing time dependence is lost in Rev-erbα knockout mice [27]. Mechanistic studies reveal that REV-ERBα generates and regulates rhythmic Ugt1a9 through periodical inhibition of DEC2, a transcriptional repressor of Ugt1a9 [27]. DEC2 trans-represses Ugt1a9 via direct binding to an E-box-like motif in the gene promoter (Fig. 6.4b) [27]. REV-ERBα also plays an important role in circadian regulation of UGT2B in mice. Knockdown (or overexpression) of REV-ERBα increases (or decreases) mRNA and protein expression of UGT2B in Hepa-1c1c7 cells [28]. Moreover, increased expression of hepatic UGT2B and disrupted rhythm are observed in REV-ERBα knockout mice [28]. A combination of luciferase reporter, mobility shift, chromatin immunoprecipitation assays demonstrate that REV-ERBα represses the transcription of Ugt2b36 through specific binding to a RevRE element in the promoter region (Fig. 6.5a) [28]. Interestingly, Ugt2b family genes (including Ugt2b1, Ugt2b5, Ugt2b35, Ugt2b36, Ugt2b37, and Ugt2b38) possess a RevRE consensus sequence, suggesting a broad regulatory action of REV-ERBα on UGT2B family enzymes (Fig. 6.5b) [28]. Morphine is a UGT2B substrate and used to treat acute and chronic pain. However, opiate withdrawal syndrome (characterized by irritability, sweating, insomnia, headache, etc.) may occur once morphine administration is discontinued [32]. Knockout of Shp (small heterodimer partner, a nuclear receptor) in mice results in downregulated UGT2B expression and therefore in increased sensitivity to morphine withdrawal syndrome [33]. The finding suggests SHP as a potential circadian regulator of UGT2B, considering that Shp is a circadian gene. Mechanistic studies uncover that SHP positively regulates Ugt2b36 expression through

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A mRNA

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WWMWM A G G T C A M T A C T A AGG T C A A A T A A A AGG T C A A T A C A C AGG T C A C A T A A A AGG T C A A A T A A A AGG T C A A A T A A A AGG T C A A

Protein

Consensus-RevRE Ugt2b1 -RevRE Ugt2b5 -RevRE Ugt2b35-RevRE Ugt2b36-RevRE Ugt2b37-RevRE Ugt2b38-RevRE

Fig. 6.5 (a) REV-ERBα represses the transcription of Ugt2b36 through specific binding to a RevRE element in the promoter region. (b) Ugt2b family genes (including Ugt2b1, 2b5, 2b35, 2b36, 2b37, and 2b38) possess a RevRE consensus sequence

Morphine withdrawal SHP

DEC 2 HNF

mRNA

1α

REV-ERBα

Hnf1 RE

RevRE

UGT2B

Protein

Morphine

Ugt2b Promoter

Morphine-3glucuronide

Fig. 6.6 SHP, REV-ERBα, DEC2, and HNF1α co-regulate rhythmic expression of UGT2B and circadian metabolism of morphine (a substrate of UGT2B)

repression of DEC2 and REV-ERBα, two negative regulators of Ugt2b36 gene [33]. REV-ERBα represses Ugt2b36 transcription via direct binding to a specific response element (located at
30/
15 bp) in promoter region of Ugt2b36, whereas DEC2 acts on Ugt2b36 expression via suppression of HNF1α-transactivation of Ugt2b36 gene (Fig. 6.6) [33].

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Circadian Clock and Sulfation Sulfation and SULTs

Sulfation (also named sulfonylation) is a phase II metabolism reaction in which a sulfonate (–SO3) group from cofactor 30 -phosphoadenosine 50 -phosphosulfate (PAPS) is transferred to the hydroxyl or amino group of substrates [34]. PAPS is a universal sulfate donor molecule required for all sulfation reactions and can be synthesized in all tissues of mammals [35]. Sulfation is an important metabolic pathway for numerous endobiotics (e.g., steroids, catecholamines, serotonin, iodothyronines, eicosanoids, some tyrosine-containing peptides, retinol, 6-hydroxymelatonin, ascorbate, and vitamin D) and xenobiotics (e.g., drugs, environmental pollutants, and dietary chemicals) [3]. The sulfated products are more water soluble and are easier to be eliminated from the body, thus sulfation is generally considered as a detoxification pathway. However, a few compounds (e.g., procarcinogens) are converted by sulfation into highly reactive intermediates that act as chemical carcinogens and mutagens via covalent binding to DNA [36]. Sulfation reaction is catalyzed by a family of enzymes called sulfotransferases (SULTs). In humans, four SULT families (SULT1, SULT2, SULT4, and SULT6) with a total number of 13 members have been identified [37]. SULT1 has nine members: SULT1A1, 1A2, 1A3, 1A4, 1B1, 1C1, 1C2, 1C3, and 1E1 [37]. SULT2 enzymes include SULT2A1, 2B1a, and 2B1b [37]. SULT4A1 and SULT6B1 are the only member of the SULT4 and SULT6 family, respectively [12]. The members of the same SULT family share at least 45% amino acid sequence identity, while members of subfamilies share >60% identity in amino acid sequence [38]. Members from the SULT1 and SULT2 families are main contributors to drug sulfation [39]. SULTs are distributed in various tissues including liver, intestine, brain, breast, jejunum, lung, adrenal gland, endometrium, placenta, kidney, and blood platelets [40]. However, some SULT enzymes show tissue-specific distribution. For example, SULT1A1 and 2A1 are highly expressed, whereas SULT1A3, 1C2, and 1C3 are not expressed in the liver [41]. SULT1A1, 1A2, 1A3, 1A4, 1B1, and 1C2 are significantly expressed in gastrointestinal tract, whereas SULT1E1, 2A1, 2B1, 1C3, and 1C4 show moderate or low distribution [42]. SULT1C1 is predominantly expressed in human fetus [43]. SULT2B is mainly localized in human prostate, placenta, adrenal gland, ovary, lung, kidney, and colon [44]. SULT4A1 is mainly distributed in the brain and SULT6B1 in the kidney and testis [45]. SULT1A1 has a broad substrate specificity, and it can metabolize various phenolic compounds (e.g., monocyclic phenols, naphtols, benzylic alcohols, and hydroxylamines), aromatic amines, drugs (e.g., afimoxifene, endoxifen, raloxifene, and fulvestrant), and opioids (e.g., buprenorphine, norbuprenorphine, pentazocine, and naloxone) [46]. Of note, p-nitrophenol has been widely used to probe the SULT1A1 activity [47]. The substrates of SULT1A2 include aromatic hydroxylamines and opioids (e.g., buprenorphine, norbuprenorphine, pentazocine, and naloxone) [3]. SULT1A3 substrates include norepinephrine, catechols, aromatic

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molecules, monocyclic phenolics (e.g., catecholamines, dopamine, demethoxycurcumin, curcumin, and vanillin), and opioids (e.g., pentazocine and naloxone). The substrates of SULT1B1 are restricted to thyroid hormones and small phenolic compounds (e.g., 1-naphtol and 4-nitrophenol) [48]. SULT1C1 metabolizes iodothyronines, and SULT1C2 metabolizes 4-nitrophenol and N-hydroxy-2acetylaminofluoren [49]. SULT1E1 is well known for its estrogen-sulfating activity. It also shows metabolic activities toward genistein, pregnenolon, iodothyronines, and 4-hydroxytamoxifen [50]. Both SULT2A and SULT2B metabolize structurally similar substrates such as dehydroepiandrosterone, but SULT2B shows a preference for cholesterol sulfation [40].

6.3.2

Circadian Rhythms in SULTs

Both mRNA and protein expression of SULT1A1 show robust diurnal variations (higher expression during the dark phase with a peak level at ZT14-18) in the liver of mice (Fig. 6.7a) [51]. Consistent with the protein levels, the liver sulfation activities toward two SULT1A1 substrates ( p-nitrophenol and galangin) are circadian time dependent with a higher activity at ZT14 than at ZT2 (Fig. 6.7a) [51]. The mRNA expression of other SULTs (e.g., Sult1b1, Sult1c2, Sult1d1, Sult1e1, Sult2a7,

Fig. 6.7 (a) Circadian variations in the expression and activities of SULT1A1. (b) Circadian patterns of Sult1b1, 1c2, 2a7, 2a8, 1d1, 1e1, and 5a1

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Sult2a8, and Sult5a1) in mouse liver shows diurnal variations, and their circadian expression can be classified into two patterns (Fig. 6.7b). Sult1b1, Sult1c2, Sult2a7, and Sult2a8 tend to obey a “daytime pattern” characterized by peaking time in the daytime. By contrast, Sult1d1, Sult1e1, and Sult5a1 follow a “nighttime pattern” characterized by peaking time in the nighttime (Fig. 6.7b).

6.3.3

Regulation of SULTs by Circadian Clock

Guo et al. investigated a potential role of the clock protein BMAL1 in circadian regulation of SULT1A1 in mice. Deletion of Bmal1 in mice blunts the circadian rhythmicity of hepatic SULT1A1 (with reduced expression levels) [51]. Likewise, BMAL1 positively regulates SULT1A1 expression in conventionally cultured Hepa1c1c7 cells, and BMAL1 knockdown blunts expression rhythmicity of SULT1A1 in serum-shocked Hepa-1c1c7 cells [51]. A combination of promoter analysis, mobility shift, and chromatin immunoprecipitation assays reveal that BMAL1 stimulates Sult1a1 transcription through its specific binding to the
571- to
554-bp region (an E-box element) in the promoter [51]. Therefore, BMAL1 activates the transcription of Sult1a1 and controls circadian expression and activity of the enzyme (Fig. 6.8) [51]. ROR and PPAR are shown to regulate hepatic SULT1E1 and SULT2A in mice [45]. Since ROR and PPAR are circadian genes, regulation by these two nuclear receptors may contribute to circadian rhythms of Sult1e1 and Sult2a1.

6.4 6.4.1

Circadian Clock and Glutathione Conjugation Glutathione Conjugation and GSTs

Glutathione conjugation is another major phase II reaction and is regarded as a defense mechanism against oxidative stress [52]. Glutathione S-transferases (GSTs) Peaking time

mRNA

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Protein

Fig. 6.8 BMAL1 trans-activates Sult1a1 through specific binding to the E-box in the promoter region

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are a family of enzymes that are responsible for glutathione conjugation. GSTs are also involved in synthesis and metabolism of arachidonic acid and steroids [53]. Human GSTs consist of three families: cytosolic GSTs, mitochondrial GSTs, and membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG family) [54]. Cytosolic GSTs are further categorized into eight major classes according to their amino acid sequence: alpha (five members), kappa (one member), mu (five members), pi (one member), theta (two members), zeta (one member), omega (two members), and sigma (one member) subfamilies [55]. Members of the same class possess greater than 40% amino acid sequence identity. Between classes, proteins have less than 25% sequence identity [56]. Alpha class of GSTs tend to metabolize small hydrophobic substrates such as 4-hydroxynonylal [57]. GST M1-1, highly expressed in the liver, metabolizes large electrophilic substrates such as the epoxide and benzo pyrene diol of aflatoxin B1 [58]. GST P1-1, the most abundant GST enzyme in red blood cells, metabolizes many endogenous substances such as acrolein, adenine, isothiocyanate, and 4-vinylpyridine [57]. Theta class of GSTs metabolize industrial carcinogens, including flat polycyclic aromatic hydrocarbons, halogenated methane, and ethylene oxide [59]. Zeta class of GST tend to metabolize α-haloacids (e.g., dichloroacetic acid) because the substrate-binding pocket is small in size and composed of polar residues [60]. Omega class of GSTs have a large and open substrate-binding pocket that can bind to polypeptide-like substrates [61].

6.4.2

Circadian Rhythms in GSTs

The first report about circadian variation in hepatic GST activity (higher levels in the dark phase) can be tracked back to 1980s. This circadian GST activity is associated with temporal variation in hepatic glutathione (GSH) level; however, the role of circadian GST expression was unexplored [62]. Zhang et al. reported circadian rhythms (the peak-to-valley ratio is up to 2.8) in mRNAs of several hepatic Gst isoforms (Gsta1/2/4, Gstp1, Gstm1/2/3/4/6, and Gstt1/2) in mice [24]. Circadian expressions of these GST mRNAs can be classified into two patterns. Gsta1/2/4, Gstp1, and Gstm1/2/3/4/6 tend to obey a “daytime pattern” characterized by peaking

Fig. 6.9 Circadian patterns of Gsta1/2/4, Gstp1, Gstm1/2/3/4/6, and Gstt1/2

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time in the daytime (Fig. 6.9). By contrast, Gstt1/2 follows a “nighttime pattern” characterized by peaking time in the nighttime (Fig. 6.9) [24]. It is noteworthy that the circadian rhythms of GST enzymes may be influenced by gender. For example, the amplitude for circadian hepatic Gstp and Gstm is higher in female than in male mice [63].

6.4.3

Regulation of GSTs by Circadian Clock

Specific deletion of Bmal1 in astrocytes led to reduced expression of several GST isoforms (i.e., Gstt1, Gstt2, Gstt3, Gsta2, Gsta3, and Gsta4) and to astrocyte activation and increased inflammatory gene expression in mice [64]. Further, increased levels of Gst expression are found in Per1/2mut mice [64]. The findings indicate regulation of Gsts by circadian clock in astrocytes. However, to date, the role of circadian clock in regulation of hepatic GSTs remains unknown.

6.5 6.5.1

Circadian Clock and Acetylation Acetylation and NATs

Acetylation is characterized by the transfer of an acetyl moiety from donor (e.g., acetyl coenzyme A) to the substrates [10]. Xenobiotic acetylation can be classified to N-, O-, and N, O-acetylation reactions [10]. N-acetylation is recognized as a major detoxification pathway for arylamines in mammals [65]. Acetyltransferases (NATs) catalyze the acetylation reactions. In humans, only two forms of xenobioticmetabolizing N-acetyltransferases (i.e., NAT1 and NAT2) have been found [66]. NAT1 has a ubiquitous tissue distribution. P-aminobenzoic acid (PABA), paminosalicylic acid, and p-aminobenzylglutamate are typical substrates of NAT1. NAT2 is mainly expressed in the liver, colon, and intestine, providing a major route for detoxification of drugs including isoniazid (an antituberculotic drug), hydralazine (an antihypertensive drug), and sulphonamides (an antibacterial drug) [67]. NAT2 tends to metabolize sulfonamides of high molecular weight owing to its large substrate-binding pocket [68].

6.5.2

Circadian Rhythms in NATs

To date, there is no report about circadian rhythm in xenobiotic metabolizing NAT1 and NAT2. However, serotonin NAT (also called aralkylamine NAT or AA-NAT, a rate-limiting enzyme in melatonin synthesis) displays a circadian rhythm in the pineal gland and retina in mammals (e.g., chickens, rats, mice, and humans)

AA-NAT

Fig. 6.10 Circadian variations of AA-NAT and melatonin

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Melatonin

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Light (rest) Dark (active)

Light (rest) Dark (active)

[69]. The expression and activity of AA-NAT peak in the dark phase (Fig. 6.10) [70]. Circadian AA-NAT accounts for the temporal variations in body melatonin level, whose pattern resembles that of AA-NAT (Fig. 6.10) [71]. As expected, AA-NAT enzyme is extremely light sensitive. AA-NAT activity is reduced to 10% within 10 min after 1 min light exposure in the dark [72].

6.5.3

Regulation of AA-NAT by Circadian Clock

There are at least three mechanisms for generation of AA-NAT rhythm. First, AA-NAT expression is directly controlled by BMAL1/CLOCK and BMAL1/ NPAS2 heterodimers (the positive limb of circadian clock) through binding to an E-box element in AA-NAT promoter [73]. Second, AA-NAT is transcriptionally regulated by adrenergic cyclic AMP (cAMP) signaling system through cAMP responsive element-binding protein (CREB, a transcriptional activator) and inducible cAMP early repressor (ICER, a transcriptional repressor) [74]. CREB action (induction of AA-NAT expression) dominates in the daytime, whereas ICER action (inhibition of AA-NAT expression) dominates in the night, thereby contributing to a diurnal oscillation in AA-NAT expression. Third, AA-NAT mRNA degradation is regulated by the three circadian proteins heterogeneous nuclear ribonucleoprotein (hnRNP) R, hnRNP Q, and hnRNP L that perform RNA-destabilizing function, resulting in an oscillation in the mRNA level [75].

6.6

Concluding Remarks

Phase II metabolism serves as an important detoxification pathway for numerous endobiotics and xenobiotics. A plenty of phase II enzymes have been shown to display temporal variations in their expressions and activities, leading to circadian metabolism and pharmacokinetics. The mechanisms for generation of rhythms in phase II enzymes appear to be rather complex. It is believed that transcriptional regulation by the components of circadian clock (e.g., BMAL1, REV-ERBα, PER, and ROR) is the main driver of rhythmic phase II enzymes. Additionally, rhythmicity of phase II enzymes may be regulated by other circadian proteins such as SHP, CREB, and hnRNP at the transcriptional and posttranscriptional levels. A better

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understanding of circadian rhythms in phase II enzymes would contribute to chronopharmacology and ultimately to chronotherapy.

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63. Xu YQ, Zhang D, Jin T, Cai DJ, Wu Q, Lu Y (2012) Diurnal variation of hepatic antioxidant gene expression in mice. PLoS One 7(8):e44237 64. Lananna BV, Nadarajah CJ, Izumo M, Cedeño MR, Xiong DD, Dimitry J et al (2018) Cellautonomous regulation of astrocyte activation by the circadian clock protein BMAL1. Cell Rep 25(1):1–9 65. Hanna PE (1996) Metabolic activation and detoxification of arylamines. Curr Med Chem 3 (3):195–210 66. Walker K, Ginsberg G, Hattis D, Johns DO, Guyton KZ, Sonawane B (2009) Genetic polymorphism in N-acetyltransferase (NAT): population distribution of NAT1 and NAT2 activity. J Toxicol Environ Health B 12(5-6):440–472 67. Kawamura A, Graham J, Mushtaq A, Tsiftsoglou SA, Vath GM, Hanna PE (2005) Eukaryotic arylamine N-acetyltransferase: investigation of substrate specificity by high-throughput screening. Biochem Pharmacol 69(2):347–359 68. Sim E, Abuhammad A, Ryan A (2014) Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br J Pharmacol 171(11):2705–2725 69. Deguchi T (1979) Circadian rhythm of serotonin N-acetyltransferase activity in organ culture of chicken pineal gland. Science 203(4386):1245–1247 70. Engel L, Vollrath L, Spessert R (2004) Arylalkylamine N-acetyltransferase gene expression in retina and pineal gland of rats under various photoperiods. Biochem Biophys Res Commun 318 (4):983–986 71. Garidou ML, Diaz E, Calgari C, Pévet P, Simonneaux V (2003) Transcription factors may frame Aa-nat gene expression and melatonin synthesis at night in the Syrian hamster pineal gland. Endocrinology 144(6):2461–2472 72. Osborne NN (ed) (2013) Selected topics from neurochemistry. Elsevier, Amsterdam 73. Haque R, Ali FG, Biscoglia R, Abey J, Weller J, Klein D (2010) CLOCK and NPAS2 have overlapping roles in the circadian oscillation of arylalkylamine N-acetyltransferase mRNA in chicken cone photoreceptors. J Neurochem 113(5):1296–1306 74. Maronde E, Pfeffer M, Olcese J, Molina CA, Schlotter F, Dehghani F (1999) Transcription factors in neuroendocrine regulation: rhythmic changes in pCREB and ICER levels frame melatonin synthesis. J Neurosci 19(9):3326–3336 75. Kim TD, Kim JS, Kim JH, Myung J, Chae HD, Woo KC et al (2005) Rhythmic serotonin N-acetyltransferase mRNA degradation is essential for the maintenance of its circadian oscillation. Mol Cell Biol 25(8):3232–3246

Chapter 7

Circadian Clock and Uptake Transporters Danyi Lu, Menglin Chen, Yi Wang, Min Chen, and Baojian Wu

Abstract Transport of drugs across biological membranes is a critical step in pharmacokinetic processes. Uptake transporters are membrane proteins that mediate the transport of a large number of drugs into cells. Because of their wide tissue distribution and broad substrate spectrum, uptake transporters are increasingly being recognized as key factors determining the pharmacokinetics of drugs and their metabolites. Altered transport kinetics of uptake transporters, caused by drug–drug interactions or functional consequences of genetic polymorphisms, may contribute to the interindividual variability in drug effects. Intriguingly, the expression of uptake transporters can be regulated by circadian oscillators, which may be associated with dosing time-dependent drug pharmacokinetics and therapeutic outcomes. In this chapter, we update current knowledge on uptake transporters that contribute significantly to drug transport and pharmacokinetics. Particularly, regulation of uptake transporters by circadian clock and the underlying mechanisms are covered. Keywords Uptake transporters · Solute carriers · Circadian clock · Drug disposition

7.1

Introduction

Drug disposition in vivo can be generally divided into four processes: absorption, distribution, metabolism, and excretion (ADME). In these processes, drug molecules need to pass through the apical and basolateral membranes, a phenomenon referred to “membrane transport”, so that they can reach various body compartments and can be cleared from the body. Membrane transport can be categorized into passive transport and active transport according to whether energy is required or not. Passive transport is the movement of substances across the membrane (using their concentration gradient) without energy expenditure. There are three types of passive D. Lu · M. Chen · Y. Wang · M. Chen · B. Wu (*) Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_7

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'IZO\KZXGTYVUXZ

Simple diffusion

Primary active transport

'*6

':6

Secondary active transport - symport Osmosis

Secondary active transport - antiport Facilitated diffusion

Fig. 7.1 Main types of passive transport and active transport

transport: simple diffusion, osmosis, and facilitated diffusion (Fig. 7.1). In contrast, active transport is the movement of substances across the membrane (usually against their concentration gradient) using energy from adenosine triphosphate (ATP) hydrolysis or downhill movement of another solute. Primary active transport and secondary active transport are two general categories of active transport (Fig. 7.1). Notably, facilitated diffusion and active transport belong to transporter-mediated membrane transport as membrane transporters are required for substance transport in these processes. Drug transporters are membrane proteins that facilitate drug movement across the cell membrane [1, 2]. Generally, drug transporters can be categorized into uptake (or influx) or efflux transporters. Uptake transporters refer to the transporters that transfer substrates into cells, whereas efflux transporters refer to the transporters that pump the substrates out of the cells. Transporters are key regulators of pharmacokinetics behaviors (and exposure) of many drugs, thus determining their efficacy or toxicity [3]. In this chapter, we focus on important uptake transporters in drug pharmacokinetics and their regulation by circadian clock system.

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7.2

133

Mammalian Drug Uptake Transporters

Uptake transporters are a class of transporters belonging to solute carriers (SLC) that transport a wide range of substrates, including endogenous and exogenous molecules and their metabolites [4]. These transporters regulate the exchange of intracellular and extracellular substances (including amino acids, sugars, steroids, lipids, and hormones), thereby playing a significant role in the maintenance of body homeostasis [5]. Also, they recognize drug molecules and mediate their uptake from extracellular medium, contributing to drug absorption and disposition [1]. The most important uptake transporters include organic anion-transporting polypeptides (OATPs/SLCOs), organic anion transporters (OATs/SLC22As), organic cation transporters (OCTs/SLC22As), organic cation/carnitine transporters (OCTNs/ SLC22As), peptide transporters (PEPTs/SLC15As), Na+/taurocholate cotransporting polypeptide (NTCP/SLC10A1), and apical sodium-dependent bile acid transporter (ASBT/SLC10A2) (Table 7.1) [1]. Members from OATP, OAT, and OCT families transport a large number of drugs and therefore are important contributors to drug pharmacokinetics, pharmacodynamics, and toxicity [6]. Drug transporters are primarily expressed in the tissues with a barrier function, such as the intestine, liver, kidney, and brain. Uptake transporters in these tissues are responsible for absorption or reabsorption of many drugs (Table 7.1). The International Transporter Consortium (ITC) has reached a consensus on the clinical significance of drug uptake transporters such as OATPs, OATs, OCTs, and other SLC transporters (Fig. 7.2) [7]. Inhibition of these transporters may lead to drug–drug interactions (DDIs) and subsequently cause severe adverse effects [8, 9]. Therefore, the ITC suggests that the interactions between chemical entities (or drug candidates) and these important uptake transporters should be evaluated in drug development and research [7]. Dysfunction of drug uptake transporters due to genetic mutations has been linked to human diseases. For example, OATP1B1 polymorphism (OATP1B1*15) has been identified as a high-risk factor for severe hyperbilirubinaemia in neonates and is also associated with the elevated serum bilirubin levels in adults [11, 12]. An OCTN1 variant (L503F) is associated with familial and sporadic inflammatory bowel disease [13]. OCTN2 mutations cause systemic carnitine deficiency due to the lack of active reabsorption of carnitine in the kidney [14]. A single nucleotide polymorphism (SNP) of ASBT, the ileal sodium-dependent bile acid transporter, is a risk factor for gallstone disease [15].

7.3

Role of Uptake Transporters in Drug Pharmacokinetics

As mentioned above (Table 7.1), a broad range of drugs are transported by uptake transporters. Accordingly, pharmacokinetics of these substrate drugs may be altered when the transporter activity is compromised (e.g., caused by genetic deficiency or

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Table 7.1 Characteristics of drug uptake transporters Tissue and cellular expression Brain (endothelial cells), kidney, intestine, liver (cholangiocytes), eye (ciliary body)

Protein OATP1A2

Gene SLCO1A2

Endogenous substrates Bile acid derivatives, bilirubin and its conjugates, and estrone sulfate

OATP1B1

SLCO1B1

Liver (hepatocytes)

Bile acid derivatives, bilirubin conjugates, and thyroxine

OATP1B3

SLCO1B3

Liver (hepatocytes)

Paraaminohippuric acid (PAH) and estrone sulfate

OATP2B1

SLCO2B1

Estrone sulfate and PAH

OCT1

SLC22A1

Liver (hepatocytes), placenta, intestine, eye Liver, small intestine, kidney, lung, skeletal muscle, brain (endothelial cells of blood– brain barrier), adipose tissue, immune cells

OCT2

SLC22A2

Kidney, small intestine, lung, placenta, thymus, brain (neurons, blood–brain barrier), inner ear

Bile acid derivatives, bilirubin conjugates, creatinine, thyroxine, acetylcholine, monoamine neurotransmitters, TEA, and MPP

OCT3

SLC22A3

Heart, skeletal muscle, brain (neurons, glial cells, plexus choroideus), small intestine, liver, lung, kidney, urinary bladder,

Estrone sulfate, PAH, creatinine, carnitine, choline, acetylcholine, monoamine neurotransmitters, and MPP

Choline, acetylcholine, thiamine, monoamine neurotransmitters, tetraethylammonium (TEA), and 1-methyl-4phenylpyridinium (MPP)

Exogenous substrates Statins, fexofenadine, methotrexate, imatinib, erythromycin, fluoroquinolones, protease inhibitors, and beta-blockers Statins, rifampin, repaglinide, methotrexate, and enalapril Statins, rifampin, digoxin methotrexate fexofenadine, enalapril, erythromycin, and taxanes Statins, amiodarone, and methotrexate Metformin, oxaliplatin, irinotecan, paclitaxel, imatinib, lamivudine, acyclovir, cimetidine, fenoterol, triptans, tropisetron, and ondansetron Metformin, oxaliplatin, cisplatin, procainamide, beta-blockers, H2 blockers (cimetidine), memantine, amantadine, zalcitabine, and lamivudine Metformin, oxaliplatin, lamivudine, lidocaine, quinidine, quinine, d-amphetamine, memantine, amantadine, ketamine, (continued)

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Table 7.1 (continued) Protein

Gene

Tissue and cellular expression

Endogenous substrates

mammary gland, skin blood vessels OCTN1

SLC22A4

Kidney, intestine, spleen, heart, skeletal muscle, brain, mammary gland, thymus, prostate, airways, testis, eye, fetal liver, sperm, immune cells Skeletal muscle, kidney, prostate, lung, pancreas, heart, small intestine, adrenal gland, thyroid gland, liver, etc.

OCTN2

SLC22A5

OAT1

SLC22A6

Kidney, placenta, brain

PAH, PGE2, taurine, pyridoxic acid, glycochenodeoxycholate sulfate, and urate

OAT2

SLC22A7

Liver, kidney

Nucleotides, neurotransmitters, PGE2, PGF2, estrogen-3-sulfate, dehydroepiandrosterone sulfate, and alphaketoglutarate

OAT3

SLC22A8

Kidney, brain, skeletal muscle, developing bone

PAH, taurine, pyridoxic acid, glycochenodeoxycholate sulfate, and estrone sulfate

Ergothioneine, carnitine, and acetylcholine

Carnitine and choline

Exogenous substrates citalopram, desipramine, and imipramine Gabapentin, pregabalin, quinidine, quinine, verapamil, ipratropium, tiotropium, and oxaliplatin

Verapamil, quinidine, levofloxacin, cephaloridine, spironolactone, imatinib, etoposide, ipratropium, valproic acid, and tiotropium Methotrexate, cimetidine, olmesartan, furosemide, penicillins, acyclovir, cidofovir, tenofovir, and zidovudine Zidovudine, paclitaxel, cimetidine, methotrexate, salicylate, bumetanide, erythromycin, tetracycline, acyclovir, ganciclovir, penciclovir, 5-fluorouracil, and allopurinol Pravastatin, rosuvastatin, cimetidine, 6-mercaptopurine, methotrexate, olmesartan, topotecan, benzylpenicillin, (continued)

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Table 7.1 (continued) Protein

Gene

Tissue and cellular expression

Endogenous substrates

OAT4

SLC22A11

Kidney, placenta, adrenal gland

Estrone sulfate, dehydroepiandrosterone sulfate, and PAH

PEPT1

SLC15A1

Small intestine, kidney, pancreas, bile duct, liver

Di- and tri-peptides, protons, melatonin

PEPT2

SLC15A2

Di- and tri-peptides, protons, melatonin

NTCP

SLC10A1

Apical surface of epithelial cells from kidney and choroid plexus; neurons, astrocytes (neonates), lung, mammary gland, spleen, enteric nervous system Liver, pancreas

ASBT

SLC10A2

Ileum, kidney, biliary tract

Bile salts, sulfoconjugated bile acids, sulfated steroids, sulfated thyroid hormones, bromosulphthalein Bile acids, taurine- and glycine-conjugated bile acids

Exogenous substrates valacyclovir, and zidovudine Zidovudine, tetracycline, bumetanide, torsemide, and methotrexate Beta-lactam antibiotics, benazepril, cefadroxil, enalapril, losartan, sulfasalazine, and valsartan Beta-lactam antibiotics, benazepril, cefadroxil, enalapril, and valacyclovir

Rosuvastatin, atorvastatin, pitavastatin, fluvastatin Dimeric bile acid analogues, benzothiazepine derivates, benzothiepene derivates, and naphthol derivates

Adapted from Refs. [1, 10], VARIDT 1.0 (http://varidt.idrblab.net/ttd/), and SLC Tables (http://slc. bioparadigms.org/)

chemical inhibition). SNPs in transporter genes may impair the transport activity thus change the pharmacokinetic profiles of their drug substrates in humans [16]. A large number of xenobiotics/drugs are potent transporter inhibitors. Co-medication with these inhibitors may alter the disposition of drug substrates [8, 9]. Highly specific (selective) inhibitors are of great value to dissect the contribution of a particular transporter to drug disposition [17]. Unfortunately, such inhibitors currently are rather limited. However, transporter-deficient or transporter-humanized animal models have been developed and used extensively to evaluate the

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Intestinal epithelia Lumen of intestine

Blood

Hepatocytes Blood OCT1

OATP2B1

OAT2 PEPT1/2

OSTα/β

OAT7 OATP1B1

ASBT ENT1/2 THTR2

HORK

OATP1B3 OATP2B1 NTCP

MCT1

ENT1/2

Kidney proximal tubules Urine

Blood

OAT4

OCT2

OCTN1/2

OATP4C1

ENT1

ENT2

PEPT1/2 THTR2 URAT1

OAT1

Brain capillary endothelial cells Blood

Brain

ENT1/2 OATP1A2 ENT2

OAT2 OAT3

Apical/luminal

Basolateral

Fig. 7.2 Important drug uptake transporters in the intestine, liver, kidney, and brain [7]

contributions of uptake transporters to drug pharmacokinetics. In this section, the important role of uptake transporters from three SLC families (i.e., OATPs, OCTs, and OATs) in drug pharmacokinetics is discussed.

7.3.1

Role of OATPs in Drug Pharmacokinetics

Human OATP family consists of 11 members: 1A2, 1B1, 1B3, 1C1, 2A1, 2B1, 3A1, 4A1, 4C1, 5A1, and 6A1 [18, 19]. Among them, OATP1B1, 1B3, 2B1, and 1A2 play important roles in drug disposition [20, 21]. OATP1B1 and 1B3 are exclusively expressed in human liver and play a significant role in hepatic drug uptake [22]. By contrast, OATP2B1 is an important determinant to intestinal drug absorption, whereas OATP1A2 influences drug transport across blood–brain barrier [22]. Statins (i.e., atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) are a class of cholesterol-lowing drugs that inhibit

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the activity of HMG-CoA reductase, the rate-limiting enzyme for de novo cholesterol biosynthesis in the liver [23]. All statins are transported by OATP transporters (e.g., OATP1A2, 1B1, 1B3, and 2B1) [24, 25]. Most statins are rapidly and extensively absorbed, and then metabolized in the liver after oral administration [23]. Hepatic uptake of statins is primarily mediated by OATP1B1, with additional contributions from OATP1B3 and 2B1 [25, 26]. mOATP1A1 (a potential homolog of human OATP1A2), mOATP1A4 (a potential homolog of human OATP1A2), mOATP1B2 (a homolog of human OATP1B1 and 1B3), and mOATP2B1 (a homolog of human OATP2B1) dominate the uptake of statins into murine liver [27]. Mice with deletion of one or more OATP genes (e.g., Slco1a1
/
, Slco1a4
/
, Slco1b2
/
, Slco2b1
/
, or Slco1a/1b
/
mice) and OATP-humanized mice (e.g., overexpression of OATP1B1 and/or OATP1B3 in wild-type or Slco1a/1b
/
mice) have been generated to study the physiological function of OATP transporters and their pharmacological relevance. These knockout and transgenic mice are fertile and develop normally without overt phenotypic abnormalities. Chen et al. reported that loss of mOATP1B2 results in lower liver-to-plasma ratios of drug concentrations for cerivastatin, lovastatin, and simvastatin, but in an increased liver-to-plasma ratio for pravastatin [28]. By contrast, Zaher et al. observed a significant decreased liver-to-plasma ratio for pravastatin in Slco1b2
/
mice compared with wild-type mice [29]. However, the reason for this discrepancy is still unclear. The liver-to-plasma ratios of atorvastatin and rosuvastatin are moderately but significantly decreased in Slco1b2-null mice [30]. In addition, Slco1b2-dificient mice show nearly 80% lower liver-to-plasma ratio for rifampin [28, 29]. Slco1a1-null and Slco1a4-null mice have been shown to have lower liver-to-plasma ratios of endogenous OATP substrates such as estradiol17β-D-glucuronide and estrone-3-sulfate [31]. However, these animals were not used to explore the in vivo contributions of mOATP1A1/1A4 to disposition of statins probably due to the lack of evidence for mouse-specific OATP1A1 and OATP1A4 in the transport of statins. In 2010, van de Steeg et al. generated a mouse model lacking all OATP1A/1B transporters (Slco1a/1b-knockout mouse) that serves as a useful tool to clarify the role of OATP transporters in disposition of endogenous substances (bilirubin and bile acids) and drugs (methotrexate and fexofenadine) [32]. Strikingly, intestinal absorption of some OATP drug substrates (e.g., methotrexate, fexofenadine, and rosuvastatin) remains unchanged in Slco1a/1b-knockout mice, excluding the contribution of intestinal OATP1A/1B transporters to the pharmacokinetics of these drugs [33]. Slco1a/1b-knockout mice show increased plasma exposure (iv: 1.6–19-fold; po: 2.1–115-fold) and decreased hepatic distribution (by >75%) for pravastatin, atorvastatin, simvastatin, and carboxydichlorofluorescein [34]. Liver-specific knockin of human OATP1B1 or OATP1B3 partially restored hepatic OATP activities, such that the pharmacokinetic profiles of these drugs were positioned between Slco1a/1b-knockout and wild-type mice [34]. In another study, Salphati et al. found that uptake of four statins (pitavastatin, rosuvastatin, pravastatin, and atorvastatin) are reduced in isolated hepatocytes from Slco1a/1b-null mice as compared to control hepatocytes [35]. Re-expression of human OATP1B1 or OATP1B3 partly restored

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the uptake ability of hepatocytes toward these statins [35]. However, re-expressed human OATP1Bs did not alter the pharmacokinetics of statins (except for pravastatin) [35]. In line with these findings, Durmus et al. observed that overexpression of OATP1B1 or OATP1B3 increased the hepatic accumulation of methotrexate while had a minor influence on its plasma concentration [36]. In comparison to Slco1a- or Slco1b-null mice, alterations in the pharmacokinetics of OATP substrates are more significant in Slco1a/1b-null mice. Human intestinal OATP2B1 may contribute to absorption of rosuvastatin because concomitant administration with ronacaleret (an OATP1B1/2B1 inhibitor) causes a 50% decrease in exposure of rosuvastatin while the Tmax and t1/2 values remain unchanged [37]. However, the hypothesis of intestinal OATP2B1 as an uptake transporter in facilitating drug absorption is contradicted by the finding that OATP2B1 is located in the basolateral membrane of human jejunum [38]. To determine whether OATP2B1 plays an important role in drug pharmacokinetics in vivo, Medwid et al. developed a mouse model with global loss of Slco2b1 gene and examined the disposition of rosuvastatin and fexofenadine (two known mouse OATP2B1 substrates). They found that pharmacokinetics of rosuvastatin after intravenous or oral administration is similar between Slco2b1-null and control mice, indicating that intestinal/hepatic mOATP2B1 has a negligible contribution to rosuvastatin disposition [39]. By contrast, deletion of mOATP2B1 reduces the Cmax and AUC0-1 values of oral fexofenadine by 70% and 41%, respectively, suggesting a predominant contribution of mOATP2B1 to intestinal absorption of fexofenadine [39]. More recently, Chen et al. showed that the AUC value of fluvastatin is decreased by ~50% after oral administration to OATP2B1-deficient mice, while accumulation of fluvastatin in the liver is not altered [40]. Consistent with this, pharmacological inhibition of OATP2B1 by erlotinib decreases the AUC of fluvastatin by about 45% in wild-type mice, but not in OATP2B1-knockout mice [40]. By contrast, erlotinib does not change the liver exposure or liver-to-plasma ratio of fluvastatin in both mouse strains [40]. These findings indicate a role of intestinal OATP2B1 in fluvastatin absorption. Taken together, OATP2B1 contributes to intestinal drug absorption in a substrate-dependent manner. Nonsynonymous SNPs of OATP transporters may influence the in vivo disposition of statins and other drugs [41]. OATP1B1*5 (521 T > C, V174A) and *15 (388A > G + 521 T > C, N130D + V174A) are two common loss-of-function variants that greatly reduce OATP1B1 activities toward statins and other OATP1B1 substrates [41]. These variants markedly attenuate the uptake of OATP1B1 substrates into the liver, resulting in decreased hepatic clearance and increased plasma concentrations. Decreased transport activity for statins caused by OATP1B1*5 and *15 polymorphisms can lead to statin-induced myopathy [26, 42]. OATP1B3 and 2B1 polymorphisms have been reported to change the pharmacokinetics of their substrates except for statins [41]. OATP inhibitors can reduce the hepatic uptake of statins and delay their systemic elimination in humans. Cyclosporine, gemfibrozil, and rifamycin SV are pan-OATP inhibitors that have been widely used to characterize the roles of OATP transporters in drug pharmacokinetics. Notably, these inhibitors also show strong inhibitory

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effects on CYP3A4 and/or CYP2C8, two main drug-metabolizing enzymes involved in metabolism of many statins. Cyclosporine coadministration increases the mean AUC values of all statins by ~2.6–20-fold in organ transplant patients [43, 44]. Gemfibrozil elevates the mean AUC values of all statins by ~1.2–4.4-fold except for fluvastatin [44]. Pharmacokinetic alterations caused by cyclosporine and gemfibrozil are probably due to OATP1B1 inhibition, since the CYP-mediated metabolism is a minor elimination pathway for statins (e.g., pitavastatin, pravastatin, and rosuvastatin) [24]. Therefore, therapeutic dosage of statins should be adjusted when an OATP inhibitor is co-administered. It should be noted that inhibition of uptake transporters can greatly alter disposition of their endogenous substrates. Inhibition of OATP1B by rifampicin elevates the plasma levels of endogenous OATP1B substrates (e.g., direct bilirubin, coproporphyrin I, hexadecanedioate, glycochenodeoxycholate-3-sulfate, and glycochenodeoxycholate-3-glucuronide) by up to ten-fold, indicating that these substrates may be used as probes to access potential OATP1B-mediated DDIs [45, 46]. It is hypothesized that the inhibition of OATP1B1 may be a crucial mechanism for drug-induced hyperbilirubinemia [47].

7.3.2

Role of OCTs in Drug Pharmacokinetics

OCT1 and OCT2, two members of the SLC22A subfamily, are important uptake transporters in regulating the disposition of many drugs. OCT1 and OCT2 are, respectively, expressed in the basolateral membrane of the hepatocytes and tubular epithelial cells. Metformin is a well-recognized substrate for OCT1 and OCT2 [48]. OCT1 mediates the hepatic uptake of metformin, while OCT2 contributes to its renal excretion [48, 49]. Metformin is mainly eliminated into urine probably because OCT2 is a high-capacity metformin transporter (10- and 100-fold greater than OCT1) and the expression level of renal OCT2 is much higher (eight-fold) than hepatic OCT1 [50]. However, OCT1 is also expressed on the apical side of human kidney proximal/distal tubules and has been shown to be associated with renal clearance of metformin [51]. Recent studies identify OCT3 as another transporter mediating the distribution of metformin in skeletal muscle and liver [52]. Intestinal absorption of metformin is a rather complex and poorly understood process that involves multiple transporters, including OCT1, OCT3, OCTN1, PMAT (SLC29A4), and THTR-2 (SLC19A3) [48]. Genetic variations of OCT transporters may change the pharmacokinetics and pharmacodynamics of metformin. In most cases, chemical or genetic modulation of OCT1 activity markedly alters hepatic metformin distribution and pharmacodynamic response, with a minor influence on systemic pharmacokinetics [53, 54]. However, it was reported that individuals carrying a loss-of-function OCT1 polymorphism (R61C, G401S, 420del, or G465R) displayed altered metformin pharmacokinetics, with a higher AUC, higher Cmax, and lower V/F [55]. An OCT2 mutation (A270S) reduces the transport activity of OCT2 and is associated with reduced renal/tubular clearance of metformin in humans [56, 57]. Several

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OCT3 variants (e.g., T44M and T400I) have been identified and they may be associated with altered metformin pharmacokinetics and pharmacodynamics [52, 58]. Mice with deletion of OCT genes have been developed and shown to be useful models for characterizing OCT functions in drug disposition and efficacy. Loss of OCT1 reduces the distribution of metformin (after intravenous administration) to mouse liver by >95% [59]. Consistently, the glucose-lowering effects of metformin are completely abolished in Slc22a1-deficient mice [60]. In addition, accumulation of metformin in the intestine was reduced in Slc22a1-deficient mice, indicating a role of OCT1 in intestinal absorption of metformin [59]. It is noteworthy that there is a difference in the expression profile of renal OCTs between human (SLC22A2) and mice (Slc22a1 and Slc22a2). Hence, it is necessary to delete both Slc22a1 and Slc22a2 genes in mice to better reflect the effect of OCT2 deficiency in humans. Higgins et al. reported that ablation of mouse OCT1/OCT2 leads to major changes in metformin clearance and volume of distribution, while the tissue drug exposure and pharmacodynamics are unaffected [61]. In OCT3-knockout mice, the bioavailability of oral metformin, along with its accumulation in skeletal muscle and adipose tissue, was markedly decreased compared with wild-type mice, accompanied by reduced plasma glucose-lowering effect [58]. In line with this, Shirasaka et al. reported that the AUC and bioavailability of metformin were significantly decreased in Slc22a3deficient mice [62]. OCT transporters are involved in the pharmacokinetics, efficacy, and toxicity of anti-cancer drugs such as cisplatin and oxaliplatin. Cisplatin is a substrate of OCT1 and OCT2 [63]. Nephrotoxicity limits the clinical use of cisplatin [64]. A nonsynonymous SNP in the OCT2 gene (A270S, rs316019) is associated with reduced cisplatin-induced nephrotoxicity in cancer patients, although the renal clearance of cisplatin is not changed [65, 66]. Co-medication of cisplatin and cimetidine (an OCT2 inhibitor) protects wild-type mice from cisplatin-induced toxicity [67, 68]. In Slc22a1/22a2-deficient mice, urinary excretion of cisplatin is decreased while the plasma levels are not altered, accompanied by reduced renal tubular damage [66]. Oxaliplatin is a substrate of OCT1, OCT2, and OCT3 [63, 69]. Loss of OCT2 reduces renal oxaliplatin excretion and oxaliplatin-induced neurotoxicity in mice [70]. In contrast, loss of OCT1 has minimal effects on the pharmacokinetics and toxicity of oxaliplatin [71]. In addition, higher expression levels of OCT1/2/3 have been linked to stronger cytotoxic effect of oxaliplatin in colorectal cancer [69, 72]. Sumatriptan is transported by hepatic OCT1 with a high capacity and this process is strongly inhibited by MPP (an OCT1 inhibitor) [73]. OCT1 polymorphisms result in a >2-fold increase in plasma sumatriptan concentration, indicating sumatriptan as a potential probe substrate for assessment of OCT1 activity [73]. Tropisetron and ondansetron are another two OCT1 substrates whose pharmacokinetic behaviors may be altered by OCT1 polymorphisms. Patients with two loss-of-function OCT1 alleles have higher plasma drug exposure and drug efficacy due to attenuated hepatic uptake of tropisetron and ondansetron [74]. The antiviral lamivudine is transported by OCT1 and OCT2, and genetic variants lead to decreased activity of OCT1 and

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OCT2 against lamivudine [75]. Notably, OCT2-mediated renal tubular secretion is a predominant elimination pathway for lamivudine in humans [76]. TEA is an endogenous substrate of OCT1 and OCT2. After intravenous administration of TEA to OCT1 knockout mice, hepatic accumulation and intestinal excretion of TEA are reduced by about 80% and 50%, respectively [77]. By contrast, excretion of TEA into urine is increased in Slc22a1 knockout mice (80% of the dose at 1 h) compared with wild-type mice (53%) [77]. The pharmacokinetics of TEA is marginally altered in Slc22a2-deficient mice [78]. In OCT1/2 double knockout mice, renal secretion of TEA is completely abolished and plasma levels are markedly increased, indicating that OCT1 and OCT2 are essential for renal secretion of TEA [78]. In addition, other endogenous substrates have been identified for OCT1 (e.g., thiamine and acylcarnitine) and OCT2 (e.g., N1-methylnicotinamide and creatinine) [17]. However, little is known about the selectivity of these endogenous substrates toward OCT1/2.

7.3.3

Role of OATs in Drug Pharmacokinetics

OAT1~4 are four most well-characterized OAT transporters involved in renal excretion/reabsorption and hepatic disposition of drugs. OAT1 and OAT3 are predominantly expressed in the basolateral membrane of the proximal tubule epithelial cells. They share overlapping substrates and contribute to the renal clearance of many endogenous substances (e.g., PAH, taurine, and glycochenodeoxycholate sulfate) and drugs (e.g., anti-cancer drugs, diuretics, and antiviral drugs). For example, methotrexate is transported by OAT1/3/4, and functional deficiency of these transporters may impair methotrexate elimination [79, 80]. Furosemide is a substrate of OAT1 and OAT3, tubular secretion of furosemide and the natriuretic responses are impaired in either Oat1 or Oat3 knockout mice [81, 82]. OAT1 and OAT3 are associated with renal excretion and toxicity of aristolochic acid. Probenecid (a potent OATs inhibitor) reduces the excretion of aristolochic acid into urine and increases its plasma concentrations, leading to attenuated kidney toxicity [83]. Loss of OAT1 or OAT3 has similar effects on the pharmacokinetics and nephrotoxicity of aristolochic acid [83]. OAT1 and OAT3 have been also implicated in cisplatin-induced nephrotoxicity. Loss of OAT1 or OAT3 in mice leads to attenuated kidney injury caused by cisplatin [84]. However, functional differences in renal OAT1/3 between human and animals may impede new drug development because data from animal models may fail to adequately predict drug-induced nephrotoxicity in humans. For example, antiviral drugs (i.e., adefovir, cidofovir, and tenofovir) interact with human OAT1 with a higher affinity (a lower Km value) than the OAT orthologs from primates and rodents [85]. Accumulation of these antiviral drugs in kidney cells may lead to toxicity, contributing to the high incidence of drug-induced kidney injury [86, 87]. However, a non-functional OAT1 variant (R454Q) does not decrease renal secretory clearance of adefovir, suggesting that other factors may contribute to urinary excretion of adefovir [88].

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OAT1 and OAT3 are able to transport a large number of endogenous substances. Eraly et al. revealed that renal secretion of the organic anion PAH is predominantly handled by OAT1 because this process is almost completely abolished in Oat1deficient mice [81]. Taurine and glycochenodeoxycholate sulfate are endogenous OAT1/3 substrates and mainly cleared through urinary excretion. Probenecid significantly inhibits renal excretion of taurine and glycochenodeoxycholate sulfate in a dose-dependent manner in humans [89]. In addition, administration of probenecid significantly decreases the renal clearance and increases the plasma AUC of pyridoxic acid in humans, suggesting that pyridoxic acid is a promising endogenous probe for OAT1/3 [90]. Vallon et al. found that creatinine is transported by mouse OAT1/OAT3 and renal secretion of creatinine was significantly reduced in Oat1/ Oat3 knockout mice [91]. In a recent publication, Nigam et al. revealed that over a hundred of endogenous metabolites are affected in the absence of OAT1 or OAT3 [92]. Many of these substances participate in various signaling pathways, including those involving lipids, bile acids, uremic toxins, and amino acids. OAT2 is an organic anion transporter and highly expressed in the liver and kidney. Although human renal OAT2 is localized to both basolateral and apical membrane of proximal tubules, rodent renal OAT2 is only expressed in the luminal/ apical side [93–95]. Hence, OAT2 is postulated to handle the renal secretion and possibly reabsorption of creatinine because it is a high-affinity transporter for creatinine [96]. It seems that OAT2, but not other uptake transporters (OAT1/3 and OCT2), mediates the active tubular secretion of guanine-containing antiviral drugs (e.g., acyclovir, ganciclovir, and penciclovir) [94]. OAT2 mediates the uptake of orotic acid via exchange with intracellular glutamate [97]. In addition, hepatic OAT2 has been shown to transport several antineoplastic drugs such as irinotecan and bendamustine [98]. OAT4 is a human-specific transporter and predominantly expressed in the kidney and placenta. OAT4 is expressed in the apical membrane of the proximal tubular cells where it is involved in renal secretion and reabsorption of many endogenous substances and drugs/xenobiotics [99, 100]. In the placenta, OAT4 is present at the basolateral (fetal) membrane of syncytiotrophoblast cells and believed to mediate the clearance of sulfated steroids from the fetal blood [101]. OAT4 is of interest due to its potential role in transporting hormones, drugs, and toxins across the maternalfetal barrier. Zhou et al. identified four OAT4 variants (L29P, R48Y, V155G, and T392I) with a reduced activity in transporting estrone sulfate [102]. These variants may impair influx or efflux of drug substrates in renal tubular and placental syncytiotrophoblast.

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Diurnal Expression and Activity of Uptake Transporters

The pharmacokinetics, efficacy, and toxicity of many drugs have been shown to be regulated by the circadian clock system. This may be attributed to the diurnal expression and activity of drug transporters and/or drug-metabolizing enzymes. In the last two decades, scientists have found that many uptake transporters are rhythmically expressed in the intestine, liver, and kidney. Furthermore, circadian expression of uptake transporters has been linked to dosing time-dependent pharmacokinetics and time-varying effects of many drugs.

7.4.1

OATPs

It has been found that the transcripts of Oatps were rhythmically expressed in mouse livers [103, 104]. The mRNA levels of Oatps tend to be higher in the light period than in the dark period. Oatp1a1, Oatp1a4, and Oatp1b2 peak at ZT9 (ZT, zeitgeber time in a 12-hour light and 12-hour dark cycle; ZT0 represents lights on and ZT12 represents lights off) with the peak-to-valley ratio ranging from 1.7 to 2.3. Oatp2b1 mRNA has a mild fluctuation over the 24-h cycle in the liver. However, Oatp2b1 is not rhythmically expressed in rat jejunum [105]. So far, there is no study testing whether the diurnal expression of OATP transporters would cause dosing timedependent pharmacokinetics and/or pharmacodynamics. Notably, a number of clinical studies have confirmed that statins, a class of typical OATP substrates, exhibit better efficacy when taken in the nighttime. We speculate a possibility that hepatic OATPs may show higher expression at night in humans, and accumulation of statins will be more extensive in the liver after nighttime administration.

7.4.2

OCTs

Oct1 mRNA oscillates in a time-dependent manner with a peak value at ZT9 [103]. As mentioned above, hepatic uptake of metformin is mainly mediated by OCT1. The acute glucose-lowing response to metformin treatment varies according to the time of day. Maximum glucose-lowing effects of metformin are achieved at ZT15 and ZT19, corresponding to the middle of the active phase for mice and late morning for humans [106]. It seems that such diurnal oscillation in metformin activity is not caused by circadian alterations in metformin pharmacokinetics because disposition of metformin in the liver is not different between ZT7 and ZT19 [106]. Whether oscillation of hepatic OCT1 contributes to chronopharmacokinetics or chronopharmacodynamics of other drugs needs further explorations.

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Oct2 is a cycling gene that may contribute to time-dependent excretion and toxicity of drugs (e.g., cisplatin) in the kidney. The mRNA and protein levels of renal OCT2 are higher at ZT6 to ZT10 compared with other circadian time points [107]. Cisplatin, an OCT2 substrate, induces time-dependent nephrotoxicity in both humans and experimental animals [107–111]. Serum blood urea nitrogen is significantly increased after injection of cisplatin at ZT2 or ZT6 in wild-type mice [107]. This is probably attributed to time-dependent pharmacokinetics of cisplatin mediated by OCT2. Indeed, higher AUC is observed when cisplatin is administrated at ZT2 than at ZT14, while the renal clearance of cisplatin is higher at ZT14 than at ZT2 [107].

7.4.3

OATs

The mRNA of Oat2 is higher between ZT5 and ZT13, with a peak-to-valley ratio of 1.6 in mouse liver [103]. The mRNA level of Oat3 demonstrates a ~2-fold oscillation in mouse kidney. The highest OAT3 expression is observed in the late light phase and early dark phase (ZT8 to ZT16) [112]. Diurnal expression of OATs in the kidney may contribute to time-dependent excretion of OAT substrates such as creatinine and furosemide because deletion of a clock gene (Bmal1) reduces the renal elimination of these OAT substrates in mice [112].

7.4.4

PEPT1

The daily fluctuations in the expression and transport activity of intestinal PEPT1 have been documented and linked to dosing time-dependent pharmacokinetics of PEPT1 substrates such as ceftibuten and carnosine. PEPT1 protein level is significantly higher at ZT12 than at ZT0 in rat intestine [113, 114]. Accordingly, intestinal absorption of an oral antibiotic ceftibuten is greater at ZT12 than at ZT0 in rats [113]. After intraintestinal administration, ceftibuten demonstrates greater Cmax and AUC at ZT12 than at ZT0 [113]. Food uptake is a key regulator of diurnal PEPT1 expression because the differences in PEPT1 protein and ceftibuten pharmacokinetics between ZT0 and ZT12 are lost after food deprivation for 2–4 days [113]. In contrast, there is no significant difference between ZT0 and ZT12 in pharmacokinetics of intravenous ceftibuten in fed or fasted rats [113]. Likewise, PEPT1 is rhythmically expressed in mouse intestine [115]. The mRNA and protein of PEPT1 increase in the light phase and decrease in the dark phase, with maximum levels at ZT10–14 [115]. Pharmacokinetic analyses reveal that the Cmax and AUC of carnosine are significantly higher after drug administration at ZT12 than at ZT0, supporting circadian time-dependent change of PEPT1 transport activity (ZT12 > ZT0).

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OCTNs

Octn1 is a circadian gene. Mouse intestinal Octn1 mRNA exhibits a robust circadian rhythm with higher levels in the light phase (highest level at ZT6) than in the dark phase [116]. OCTN1 protein peaks at the beginning of dark phase (ZT14), indicating a delay (about 8 h) in the translation of mRNA to protein product. The transport activity of intestinal OCTN1 also shows a diurnal fluctuation. Gabapentin, a typical substrate of OCTN1, displays time-dependent accumulation (ZT14 > ZT2) in the small intestine of mice. As a result, the Cmax and AUC of gabapentin after oral administration are higher at ZT14 dosing than at ZT2 dosing. However, chemical inhibition of OCTN1 abolishes the diurnal variation in gabapentin transport. These findings reveal that the diurnal rhythmicity in intestinal OCTN1 can alter the pharmacokinetics of OCTN1 substrates. OCTN1 is also highly expressed in the kidney and contributes to the reabsorption of endogenous substances and drugs. However, whether OCTN1 is rhythmically expressed in the kidney remains unknown. The expression of Octn2 does not show circadian rhythm in rat intestine [105]. It is not clear whether OCTN2 is diurnally expressed in other tissues.

7.4.6

ABST and NTCP

ABST and NTCP are the principal uptake transporters mediating the absorption of bile acids in the intestine and liver, respectively. Both transporters show higher expression in the dark period in mice, facilitating the absorption of bile acids and lipids after food intake in the active phase [117].

7.4.7

MCTs

The blood lactate level displays significant circadian rhythm (ZT15 > ZT3) [106]. Lactate transport is mediated by MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8), and MCT4 (SLC16A3). Both Mct1 and Mct2 genes show diurnal expression in mouse liver, and their loci are bound by all examined circadian clock regulators [118]. The mRNA level of Mct1 in mouse liver decreases in daytime and increases in nighttime, with a lowest level at ZT12 [106]. In contrast, the mRNA level of Mct2 in mouse liver increases after light on and reaches the highest level at ZT16 [106]. Therefore, daily fluctuations of blood lactate may be attributed to rhythmic expression of MCT1/MCT2.

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Hexose Transporters

In the small intestine, uptake of glucose and galactose are driven by apical SGLT1 (SLC5A1) and GLUT5 (SLC2A5) and basolateral GLUT2 (SLC2A2) transporters. These hexose transporters display obvious diurnal expression in the intestine of rodents, with the highest mRNA levels near the onset of dark phase [114, 119– 122]. Absorption of glucose is low in daytime and high in nighttime in rats fed ad libitum [123]. In line with this, glucose uptake is significantly higher at ZT15 than other time points in mice jejunum (i.e., ZT3, ZT9, and ZT21) [124]. Phloridzin (a specific inhibitor of SGLT1) reduces glucose uptake and completely abolishes its rhythmicity, highlighting SGLT1 as a determinant to diurnal glucose uptake [124]. The rhythmicity in hexose transporters and glucose absorption may be caused by the feeding cycle (independent of the light cycle) [125]. Mice undergoing restricted feeding with access to food only in the light period completely reverses the expression patterns of these hexose transporters [119].

7.4.9

NPTs

Inorganic phosphate (Pi) is an essential nutrient for living organisms. NPT2a (SLC34A1), NPT2b (SLC34A2), and NPT2c (SLC34A3) are sodium phosphate cotransporters that play a major role in absorption/reabsorption of Pi in the intestine (NPT2b) and kidney (NPT2a and NPT2c) [126]. In humans and rodents, the plasma concentrations and urinary excretion of Pi display significant daily oscillations [127– 130]. Human serum Pi level peaks between 2:00 AM and 4:00 AM and reaches a nadir between 8:00 AM and 10:00 AM [128, 130]. The diurnal oscillation of plasma Pi level in nocturnal mice is nearly anti-phase to that in humans (with the highest concentration at ZT10 and the lowest level at ZT18) [129]. On the other hand, the level of urinary Pi increases in the resting phase and decreases in the active phase with a peak level at ZT14 [129]. Intriguingly, renal NPT2a and intestinal NPT2b show significant diurnal rhythms with similar patterns (i.e., gradually decreases from ZT2 to ZT14 and then increases until ZT22, the lowest level at ZT14), while renal NPT2c protein shows a higher level at ZT10 compared with other circadian time points. Consistently, the renal/intestinal Pi transport activity in isolated brush border membrane vesicles is significantly higher at ZT2 than at ZT14. Loss of Npt2a decreases plasma Pi level and increases urinary Pi excretion at all circadian time points, however, the Pi level still displays a circadian rhythm. Double deletion of Npt2a and Npt2c completely abolishes the daily oscillations of plasma Pi level and urinary Pi excretion, suggesting that both NPT2a and NPT2c are indispensable to circadian Pi homeostasis. In addition, NPT2b may contribute to circadian Pi homeostasis because intestine-specific deletion of Npt2b significantly reduces urinary Pi excretion. Notably, knockout of Npt2 gene in mice has no influence on food intake, a key factor regulating diurnal Pi concentrations [129, 131].

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7.4.10 SLC19A1 SLC19A1 is a folate transporter which is ubiquitously expressed in mammalian tissues. Recent studies reveal that SLC19A1 plays a significant role in cellular uptake of cyclic dinucleotides (e.g., cGAMP) and methotrexate [132, 133]. SLC19A1 polymorphisms have been shown to alter methotrexate toxicity, which may account for discontinuation of methotrexate treatment [134– 136]. Expression of Slc19a1 displays a strong rhythm in mouse liver [137]. Slc19a1 mRNA increases in the daytime and decreases in the nighttime, with the highest level at ZT10–14 [137]. However, the effects of circadian clock system on the protein and transport activity of SLC19A1 remain unknown.

7.5

Regulation of Uptake Transporters by Circadian Clock Components

In general, the diurnal rhythmicity in gene expression is generated and regulated by circadian clock genes (i.e., BMAL1, CLOCK, E4BP4, DBP, REV-ERBs, and RORs) via direct binding to the cis-elements (i.e., E-box, D-box, and RevRE or RORE) located in the promoter regions of target genes [138]. Such regulatory mechanism may be also applicable to the generation of diurnal rhythmicity in expression of uptake transporters. In addition, it has been found that certain nuclear receptors (e.g., PPARα) are contributors to diurnal expression of uptake transporters.

7.5.1

OATPs

A recent study reported that ablation of Bmal1 did not change the expression and circadian patterns of OATP1A1 and OATP1B2 in mouse liver, indicating that BMAL1 is not a regulator of these cycling OATPs [104]. However, the contributions of other circadian clock components to the rhythms of OATPs have not been explored. Due to a significant role of OATP transporters in drug pharmacokinetics and pharmacodynamics, scientists are encouraged to elucidate the molecular mechanisms underlying the diurnal expression of OATP transporters in the future.

7.5.2

OCTs

A genome-wide scale analysis has shown that several circadian regulators, including CLOCK, BMAL1, CRY1, CRY2, and PER2, bind to the promoter region of Oct1 gene in mouse liver [118]. However, whether and how these clock genes regulate the

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expression of OCT1 are not clear. Henriksson et al. recently reported that Oct1 mRNA did not show a diurnal rhythm in mouse liver, and loss of Bmal1 did not alter the expression of OCT1 [106]. Daily oscillation of OCT2 may be regulated by CLOCK, PPARα, RORα, and PER1/2. Clock ablation in mice leads to down-regulated OCT2 expression, and to reduced renal excretion and increased exposure (AUC) of cisplatin as well as increased nephrotoxicity [107]. CLOCK regulates OCT2 expression through the cycling nuclear receptor PPARα. PPARα binds to a PPRE element in Oct2 promoter and promotes the transcription of Oct2 in a time-dependent manner in wild-type mice [107]. Deletion of Clock reduces PPARα expression and abolishes its regulation effect on OCT2. In addition, knockout of PPARα not only decreases the renal clearance of cisplatin but also abolishes the diurnal variations in renal cisplatin excretion [107]. Oct2 promoter also contains several RORE elements to which RORα can bind. Overexpression of RORα enhances the transcriptional activity of Oct2 promoter, indicating that the circadian oscillator RORα may contribute to the diurnal expression of OCT2 [107]. Besides, OCT2 may be regulated by PER1/2 because the temporal variation in cisplatin-induced toxicity is lost in Per1/2-deficient mice [111].

7.5.3

OATs

BMAL1 is a circadian regulator of OAT3 expression. Oat3 mRNA is remarkably reduced after specific knockout of Bmal1 in renal tubular cells [112]. Consistently, Bmal1 deficiency results in an approximate 80% decrease in the level of OAT3 protein. This is paralleled by a significant increase in plasma creatinine concentration and a decrease in renal secretion of furosemide [112]. However, little is known about regulation of other OAT transporters by the circadian clock system.

7.5.4

PEPT1

The clock components (e.g., CLOCK and DBP) and bile acid-PPARα pathway contribute to diurnal expression of PEPT1. Mutation of Clock gene significantly decreases Pept1 mRNA level in mouse intestine [139]. In addition, Clock ablation in mice disrupts the rhythmic expression of PEPT1 [139]. By contrast, deletion of Per2 does not change the diurnal expression [115]. Saito et al. reported that circadian oscillation of PEPT1 may be driven by the clock-output transcription factor DBP in rats [140]. The expression of PEPT1 is in phase with that of DBP, and DBP transactivates Pept1 gene via direct binding to a D-box element in the gene promoter [140]. PPARα activates intestinal expression of Pept1 mRNA through binding to a PPRE element in Pept1 promoter [115]. Bile acids suppress PPARα-mediated

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transactivation of Pept1 through interfering with coactivator recruitment in a timedependent manner, leading to diurnal expression of intestinal PEPT1 and daily variations in intestinal absorption of small peptides. Knockout of Pparα in mice significantly reduces PEPT1 expression and abrogates its rhythm. In line with this, the plasma exposure of carnosine (dosing at ZT12) in Pparα-deficient mice is markedly lower than that in wild-type mice [115]. It should be noted that food intake greatly affects the diurnal rhythm of PEPT1 expression [141]. Food deprivation abolishes the rhythmicity in PEPT1 expression, and refeeding restores its diurnal oscillation [141]. Feeding stimulates the release of bile acids into the intestine, and then bile acids accumulate and suppress the PPARα pathway in intestinal epithelial cells in a feeding-dependent manner.

7.5.5

OCTN1

The mechanisms for diurnal expression and activity of OCTN1 transporter are poorly understood. PPARα directly activates the transcription of mouse Octn1, and two PPRE elements in Octn1 gene promoter are identified to respond to the activation by PPARα [116]. In the dark phase, food uptake results in accumulation of bile acids (PPARα inhibitors) in intestinal epithelial cells, which suppresses the transactivation of Octn1 [116]. Time-dependent suppression of PPARα-mediated transactivation by bile acids generates oscillations in intestinal expression of OCTN1. Interestingly, the mRNA and protein levels of OCTN1 are rhythmically expressed in cholic acid-shocked aMoS7 cells. In addition, accumulation of gabapentin in cholic acid-shocked aMoS7 cells displays a significant diurnal rhythm, which is correlated with the expression profile of OCTN1 protein. To date, whether OCTN1 is directly regulated by circadian clock genes remains unknown.

7.5.6

MCTs

BMAL1 transcriptionally regulates the expression of MCT1 and MCT2. The mRNA levels of Mct1 and Mct2 are, respectively, increased and decreased in Bmal1knockout mice as compared with wild-type mice [106]. However, ablation of Bmal1 has no influence on blood lactate measured at ZT7 and ZT19 [106].

7.5.7

Hexose Transporters

The circadian components CLCOK, BMAL1, and PER1 have been identified as regulators of rhythmic expression of SGLT1. Ablation of CLCOK significantly increases SGLT1 expression, and abolishes its rhythmicity in mouse intestine

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[115, 139]. CLOCK can directly bind to E-boxes in Sglt1 promoter in kidney cells [142]. Knockdown of BMAL1 increases SGLT1 expression and glucose uptake, while overexpression of BMAL1 decreases SGLT1 expression and glucose uptake [143]. BMAL1 can directly and rhythmically bind to the proximal promoter (E-box regions) of Sglt1 gene in mouse intestine [119]. BMAL1 controls SGLT1 expression through PAX4, a transcriptional repressor that directly binds to the HIF1α-binding site of SGLT1 promoter in Caco-2 cells [143]. Pharmacological inhibition or genetic deletion of PER1 results in decreased expression of SGLT1 in kidney cells [142]. PER1 directly interacts with three E-boxes in SGLT1 promoter as revealed from ChIP-PCR experiments [142]. In contrast, Balakrishnan et al. found that knockdown of PER1 increased SGLT1 expression in Caco-2 cells [144]. They also found that regulation of SGLT1 by PER1 is E-boxes-independent in Caco-2 cells because mutation of E-boxes has a negligible effect on PER1-mediated suppression of SGLT1 expression [144]. Glut2 and Glut5 genes contain multiple E-boxes that are directly recognized by the clock components BMAL1 and CLOCK. Binding of BMAL1 to the promoter/ enhancer and transcribed regions of Glut2 and Glut5 genes varies according to time of the day [119]. Glut2 and Glut5 mRNAs are moderately increased and their rhythms are abolished in the intestine of Clock mutated mice [139]. Therefore, BMAL1 and CLOCK contribute to the diurnal expression of GLUT2 and GLUT5.

7.6

Concluding Remarks

Uptake transporters play a significant role in disposition of endogenous substances and xenobiotics including drugs. These proteins are also important regulators of drug efficacy and toxicity. Many uptake transporters are rhythmically expressed in the intestine, liver, and/or kidney, thus their activities vary according to time of the day. It is becoming clear that the rhythms of uptake transporters can be translated to circadian pharmacokinetics and drug effects that have direct implications for chronotherapeutics. Although the circadian oscillators such as CLOCK, BMAL1, and/or PPARα have been shown to regulate the rhythms of uptake transporters (e.g., OCT2, PEPT1, and GLUT2), the underlying molecular mechanisms have not been fully established. Additionally, the current data about circadian uptake transporters are mainly derived based on rodents. Future studies may be directed to elucidate the mechanisms for circadian clock regulation of uptake transporters, and to verify whether the animal data can be translated to humans.

References 1. Priyadarshini R (2019) Drug transporters. In: Introduction to basics of pharmacology and toxicology. Springer, Cham, pp 155–176

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Chapter 8

Circadian Clock and Efflux Transporters Danyi Lu, Huan Zhao, and Baojian Wu

Abstract Efflux transporters from the ATP-binding cassette (ABC) and solute carrier (SLC) families [e.g., P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance proteins (MRPs), and multidrug and toxin extrusions (MATEs)] are key determinants to the disposition of endogenous and exogenous compounds. Their expression and activity have been shown to oscillate according to time of the day in tissues with a barrier function, such as intestine, liver, kidney, and brain. Such diurnal oscillations are regulated by the circadian timing system which is composed of multiple transcriptional factors (e.g., BMAL1 and CLOCK). Accumulating evidence supports that daily fluctuations in the activities of efflux transporters are associated with dosing time-dependency in pharmacokinetics and drug effects. In this chapter, we review circadian regulation of efflux transporters and its influences on drug disposition, toxicity, and efficacy. Keywords Efflux transporters · Circadian rhythm · Pharmacokinetics · Drug toxicity and efficacy · Dosing time

8.1

Introduction

Drug molecules generally traverse cell membrane and enter the cells through passive diffusion or transporter-mediated uptake. After entering into cells, drug molecules may undergo phase I and/or phase II metabolism. Subsequently, drugs and their metabolites are transported out of cells via efflux transporters localized in the cell membrane. Efflux transporters belong to ATP-binding cassette (ABC) transporter superfamily, with the exception of multidrug and toxin extrusions (MATEs/ SLC47As) that are solute carrier (SLC) members [1, 2]. These transporters are highly expressed in barrier epithelia and play a significant role in mediating the D. Lu · H. Zhao · B. Wu (*) Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_8

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movement of endogenous and exogenous substances (including drugs) between body fluid compartments and tissues. For example, movement between blood and urine, blood and bile, blood and brain, and blood and placenta. As a result, efflux transporters are dominant regulators of drug disposition, and contribute significantly to drug efficacy and toxicity. Inter-individual difference in response to drug treatment is a major problem in pharmacotherapy. Efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance proteins (MRPs), and MATEs have been reported to account for inter-individual variations in pharmacokinetics and drug effects as well as clinical drug–drug interactions. Intriguingly, the time of drug administration is increasingly recognized as a contributor to variations in pharmacokinetics and pharmacodynamics, which has implications for design of optimal therapeutic schedules. Dosing time-dependent pharmacokinetics and drug effects may be attributed to diurnal oscillations in the expression and activities of efflux transporters. In this chapter, we focus on current knowledge about the role of efflux transporters in drug disposition and pharmacokinetics. Moreover, we provide recent advances in regulation of efflux transporters by circadian clock.

8.2

Mammalian Drug Efflux Transporters

In mammals, efflux transporters are highly conserved proteins that are predominantly expressed in gastrointestinal tract, hepatobiliary system, kidney, and central nervous system (Table 8.1 and Fig. 8.1). These transporters pump the substrates out of cells (and reduce their intracellular accumulation) by using energy generated from ATP hydrolysis or downhill movement of another solute. Because of their significant roles in drug pharmacokinetics and drug–drug interactions, efflux transporters (e.g., P-gp, BCRP, MRPs, and MATEs) should be evaluated in drug development and research processes as noted by the International Transporter Consortium (ITC) (Fig. 8.1).

8.2.1

P-Glycoprotein/ABCB1

P-glycoprotein (P-gp/ABCB1/MDR1), a 170 kDa plasma membrane protein, is one of the most well-characterized efflux transporters. Like other ABC transporters, P-gp is composed of two transmembrane domains (TMDs) and two cytoplasmic nucleotide-binding domains (NBDs, where ATP binding and hydrolysis take place). P-gp is predominantly expressed in enterocytes, kidney proximal tubule, hepatocytes (canalicular), and brain endothelia. It mediates the transportation of the drug substrates from intracellular to extracellular compartment, thereby limiting cellular drug accumulation and protecting tissues from drug-induced injury. P-gp has a wide substrate spectrum, including chemotherapeutic drugs (e.g.,

Hepatocytes (basolateral membrane), choroid plexus (epithelium), renal proximal tubule (apical membrane), and brain (capillary endothelium)

MRP4 (ABCC4)

MRP3 (ABCC3)

Hepatocyte (canalicular membrane) and renal proximal tubule (apical membrane of endothelial cells), apical membrane of the small intestine, gallbladder, and placenta Hepatocytes (basolateral membrane), kidney distal tubules, ileal and colonic enterocytes, cholangiocytes, gallbladder, pancreas, spleen, and adrenal cortex

Location Intestinal enterocytes, kidney proximal tubule, hepatocytes (canalicular), brain endothelia Kidney, lung, testis, cardiac and skeletal muscle, and placenta

MRP2 (ABCC2)

MRP1 (ABCC1)

Transporter protein (gene) P-gp (ABCB1)

Cyclic nucleotides, glutathione conjugates, eicosanoids, urate, folate, bile acids, and conjugated steroids

Taurocholate, cholate, glycocholate, bilirubin glucuronide, folic acid, estradiol-17-glucuronide, LTC4, 3-sulfate conjugates (such as taurocholate, dehydroepiandrosterone)

Conjugates of glutathione, glucuronide and sulfate, bile salts, estradiol, and organic anions Conjugates of glutathione, glucuronide and sulfate, bile salts, estradiol, and organic anions

Endogenous Steroids, lipids, bilirubin, and bile acids

Substrates

Table 8.1 Characteristics of human efflux transporters

Teniposide, etoposide, leucovorin, methotrexate, vincristine, etoposide, cefadroxil, fexofenadine, ethinylestradiol glucuronide, morphine 3- and 6 -glucuronide, and paracetamol glucuronide and sulfate Anticancer drugs (6-mercaptopurine, methotrexate), antiviral drugs (adefovir, tenofovir), diuretics (furosemide, trichlormethiazide), and cephalosporins

Anticancer drugs (methotrexate, vinca alkaloids, anthracyclines, melphalan), statins, and antiviral drugs

Exogenous Digoxin, loperamide, berberine, irinotecan, doxorubicin, vinblastine, paclitaxel, and fexofenadine Anticancer drugs, statins, and antiviral drugs

MK-571

(continued)

Methotrexate, mitoxantrone, probenecid, etoposide

MK-571, cyclosporine, probenecid, indomethacin, LTC4, furosemide, and grapefruit juice

MK-571, LTC4, sulfinpyrazone, benzbromarone, and probenecid

Inhibitors Cyclosporine, quinidine, tariquidar, verapamil

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Canalicular membrane of hepatocytes

Proximal convoluted tubules (apical membrane), hepatocytes (canalicular membrane), and skeletal muscle

Proximal convoluted tubules (apical membrane)

MATE1 (SLC47A1)

MATE2-K (SLC47A2)

Location Intestine (luminal membrane of enterocytes), liver (canalicular membrane), kidney, organs with barrier functions (brain, testis, placenta), and mammary glands

BSEP (ABCB11)

Transporter protein (gene) BCRP (ABCG2)

Table 8.1 (continued)

Guanidine, thiamine, N-methyl nicotinamide (NMN), tetraethyl ammonium (TEA), 1-methyl-4phenylpyridinium (MPP), and creatinine

Taurochenodeoxycholate taurocholate, glycocholate, tauroursodeoxycholate

Endogenous Porphyrins, estrogen sulfate, and uric acid

Substrates

Metformin, fexofenadine, topotecan, and some anionic drugs like acyclovir and ganciclovir, cephalexin, cephradine, and paraquat Metformin, fexofenadine, topotecan, and some anionic drugs like acyclovir and ganciclovir

Exogenous Anticancer agents (anthracyclines, imatinib, topotecan, methotrexate), prazosin, pantoprazole, antibiotics (nitrofurantoin, fluoroquinolones), and statins Pravastatin

Cyclosporine, ritonavir, rosiglitazone, saquinavir, troglitazone, ketoconazole, pioglitazone, lovastatin, haloperidol, atorvastatin, and chlorpromazine Cimetidine, quinidine, procainamide, tyrosine kinase inhibitors, and pyrimethamine

Inhibitors Cyclosporine, omeprazole, pantoprazole saquinavir, and tacrolimus

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Intestinal epithelia Lumen of intestine

Blood

MRP3

MRP2 BCRP

MRP3

MRP4

HORK MRP6

P-gp

Kidney proximal tubules Urine

Hepatocytes Blood

Blood

Brain capillary endothelial cells Blood

Brain

MRP2 MRP4 P-gp MATE1

MRP4

BCRP P-gp

MATE2-K

Apical/luminal

Basolateral

Fig. 8.1 Major efflux transporters in the intestine, liver, kidney, and brain [3]

5-fluorouracil), calcium channel blockers (e.g., azidopine), immunosuppressive agents (e.g., cyclosporin A), antiarrhythmics (e.g., loperamide), HIV protease inhibitors (e.g., saquinavir), antihistamines (e.g., cimetidine), antibiotics (e.g., cefoperazone), natural products (e.g., aristolochic acid), and fluorescent dyes (e.g., calcein acetoxymethyl ester). The major functions of P-gp include the following: (1) it plays a significant role in pharmacokinetic processes (absorption, distribution, and excretion) and clinical drug–drug interactions; (2) it reduces the bioavailability of drugs; (3) it mediates the excretion of substrates into the bile and urine; and (4) it limits the entry of toxic compounds and drugs into the central nervous system. Induction or inhibition of P-gp may lead to drug–drug interactions. For instance, disposition of oral digoxin is determined by intestinal P-gp, thus concomitant administration of rifampin (a P-gp inducer) reduces digoxin (oral administration) exposure and decreases its therapeutic efficacy [4]. P-gp mediates renal elimination of digoxin, thus inhibition of P-gp with verapamil (a known P-gp inhibitor) significantly decreases the renal elimination and increases the plasma concentration of digoxin [4, 5].

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Absence of P-gp is harmless to the lives under normal conditions, but this may increase the toxicity in response to drug treatment. Mdr1 gene is frequently mutated (a 4-bp deletion) in collies (a dog breed), generating several stop codons that prematurely terminate P-gp synthesis and therefore lead to a total loss of P-gp activity [6]. Homozygous carriers are apparently healthy (showing no physiological abnormalities), but treatment with ivermectin (an antihelminthic drug) leads to severe neurotoxic effects [6]. The same situation is also observed in mdr1a/b double knockout mice [7]. Mdr1a/b-deficient mice develop normally and are viable and fertile [7]. However, loss of mdr1a/b significantly alters the pharmacokinetics of P-gp substrates in mice [7]. No loss-of-function variant of P-gp has been identified in humans, possibly due to a critical role of P-gp in xenobiotic detoxification. Human ABCB1 gene possesses a number of SNPs. The frequency and functional consequences of 3435C>T, 2677G>T/A, and 1236C>T are of greatest concern [8]. 3435C>T polymorphism (13.3% in Caucasian) is associated with a low P-gp expression in the intestine and higher exposure of digoxin [9]. It should be noted that the expression of P-gp is transcriptionally regulated by several nuclear receptors (e.g., pregnane X receptor, constitutive androstane receptor, and vitamin D receptor) [10]. However, influences of ABCB1 mutations on regulation of P-gp expression by these nuclear receptors are still unknown. P-gp substrates (e.g., cyclosporine, digitoxin, and vinblastine) are usually metabolized by CYP3A4 [11]. Besides, both P-gp and CYP3A4 are highly expressed in the intestine and liver. The overlaps in tissue distribution and substrate specificity indicate that P-gp may cooperate with CYP3A4 in determining the bioavailability of drugs. To verify this hypothesis, Carolyn et al first investigated the metabolism and transport of K77 (a P-gp and CYP3A4 substrate) and felodipine (a CYP3A4 substrate only) in CYP3A4-transfected Caco-2 cells [12]. Cyclosporine (an inhibitor of CYP3A4 and P-gp) and GG918 (an inhibitor of P-gp only) enhance K77 metabolism [12]. Metabolism of felodipine is unchanged in the presence of GG918 but decreased by cyclosporine [12]. In addition, K77 absorption is significantly increased (4.2- to 5-fold) in the presence of cyclosporine and GG918, whereas no change is observed for felodipine [12]. This CYP3A4/P-gp interplay is further confirmed by a number of studies using in silico (e.g., physiologically based pharmacokinetic models), in vitro (e.g., transfected cell lines), ex vivo (e.g., isolated tissues), in situ (e.g., perfused organs), and in vivo (knockout and transgenic mice) models [13–17].

8.2.2

MRPs/ABCCs

The ABCC family consists of 13 members, termed as MRP1-MRP9 (encoded by ABCC1-ABCC6 and ABCC10-ABCC12), CFTR (ABCC7), SUR1 (ABCC8), and SUR2 (ABCC9). Of the nine MRP proteins, four (MRP4, 5, 8, 9) have a typical ABC structure with two transmembrane segments and two nucleotide-binding domains. Others (MRP1, 2, 3, 6, 7) have an extra N-terminal transmembrane domain.

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MRPs are ATP-dependent efflux pumps that transport a broad spectrum of endogenous and xenobiotic anionic substances [10]. Prototypical substrates include bilirubin glucuronides (for MRP2 and MRP3), glutathione conjugates such as leukotriene C4 (for MRP1, MRP2, and MRP4), and cyclic AMP/GMP (for MRP4, MRP5, and MRP8) [18–20]. In addition, MRPs can confer cell resistance to toxic substances (toxins and drugs) through mediating substrate efflux from intracellular to extracellular compartment [21]. Interestingly, substrate specificities of several MRPs are modified by reduced glutathione (GSH), a tripeptide present in living cells at high concentrations (in a millimole range). For example, vincristine is cotransported with GSH by MRP1; bile acids and leukotriene B4 are cotransported with GSH by MRP4 [20, 22–24]. Efflux of conjugate metabolites, often generated from phase II reactions, represents the final step in the detoxification pathway for many xenobiotics and endogenous substances. The pathophysiological role of MRP proteins can be illustrated by their significance in mediating the release of proinflammatory and immunomodulatory mediators such as leukotrienes and prostanoids [25–27]. Genetic variants with a functional defect in MRP protein are associated with pathophysiological consequences. For instance, hereditary MRP2 deficiency (impaired MRP2 protein maturation or sorting) causes Dubin-Johnson syndrome, which is a form of hyperbilirubinemia, due to impaired transport of conjugated bilirubin into bile [28, 29]. MRP4 (ABCC4) polymorphisms are associated methotrexate-induced toxicity in pediatric patients with acute lymphoblastic leukemia [30]. Mutations in MRP6 (ABCC6) gene may cause pseudoxanthoma elasticum, a rare heritable disorder, resulting in the calcification of elastic fibers [31, 32]. SNPs in the MRP8 (ABCC11) gene are determinants of human earwax type and osmidrosis [33, 34]. MRP1 is highly expressed in human lung, testis, kidney, and placenta [35– 37]. Notably, MRP1 is localized in either apical membrane (e.g., placenta) or basolateral membrane (e.g., bronchial epithelium) [38–40]. MRP1 is expressed at a low level in the luminal membrane of human brain capillary endothelial cells, and its contribution to the function of the blood–brain barrier is still controversial. Due to ubiquitous expression and broad substrate specificity, genetic variants of MRP1 gene have received enormous attention. To date, dozens of MRP1 missense variants have been identified in ethnic populations, and some of them lead to altered expression and/or transport activity of MRP1. Certain ABCC1 variants are associated with increased susceptibility to cancers, while others are correlated with treatment outcome or adverse effects of drugs (e.g., doxorubicin, methotrexate, and irinotecan). For instance, R723Q variant is associated with a 3.4-fold increased risk of lung cancer in Chinese population [41]. G671V variant is correlated with doxorubicininduced cardiotoxicity in non-Hodgkin lymphoma patients [42]. MRP2 is exclusively localized in the apical (canalicular) membrane of polarized human/rodents cells, such as hepatocytes, kidney proximal tubules, small intestine, colon, gallbladder, bronchi, and placenta [40, 43–50]. This is in line with its role as a conjugate efflux pump in mediating the excretion of many conjugated products of endogenous substances and drugs into extracellular fluids such as bile, urine, and intestinal fluid. Polymorphisms in ABCC2 may change the expression, location, and

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function of MRP2, which are associated with Dubin-Johnson syndrome and other diseases (e.g., nonalcoholic fatty liver disease) [28, 29, 51]. In addition, ABCC2 variants may lead to an alteration in the pharmacokinetics or toxicity of drug substrates such as methotrexate (rs2273697, V417I), statins (rs717620, 50 -UTR), and carbamazepine (rs2273697, V417I) [52–55]. MRP3 is localized in the basolateral membrane of many polarized cells, including hepatocytes, kidney distal tubules, enterocytes, cholangiocytes, gallbladder, pancreas, spleen, and adrenal cortex [49, 56–59]. Interestingly, hepatic expression of MRP3 is significantly induced when MRP2 is absent. This is originally seen in Mrp2-deficient rats with conjugated hyperbilirubinemia, in which secretion of bilirubin glucuronides into bile is severely limited [60]. Similarly, hereditary MRP2 deficiency in Dubin-Johnson syndrome and various types of cholestatic liver diseases may lead to increased MRP3 levels in human liver, which may explain a large inter-individual variation in the MRP3 level (up to 80-fold) [56, 61, 62]. These hepatic disorders are often associated with elevated serum concentrations of bilirubin glucuronides, which are normally secreted into bile by the apical conjugate efflux pump MRP2. Therefore, MRP3 is a basolateral efflux pump which compensates for the elimination of bilirubin glucuronides when the activity of MRP2 in the canalicular membrane is impaired [56, 63]. A number of ABCC3 variants (including 18 nonsynonymous variations) have been identified in different populations, while only few of them are associated with changes in transporter expression, localization, or activity [61, 63–65]. A promoter mutation (rs4793665, 211C>T) leads to a significantly lower ABCC3 mRNA level in human liver [61]. This variant may serve as a predictor for the prognosis or clinical outcome of chemotherapy in cancer patients [66, 67]. In addition, this variant is associated with a better response to methotrexate in juvenile idiopathic arthritis [68]. MRP4 is localized in the basolateral or apical membrane of polarized cells depending on the cell type [69]. Basolateral localization of MRP4 is seen in glandular epithelial cells of the prostate, hepatocytes, pancreatic duct epithelial cells, and choroid plexus epithelial cells, while apical/luminal localization of MRP4 in proximal tubule epithelial cells and brain capillary endothelial cells [19, 24, 58, 70–72]. Genetic polymorphisms of MRP4 have been identified in ethnic populations [64, 73–77]. Of note, MRP4 variants are associated with changes in disease susceptibility, drug pharmacokinetics, adverse drug reactions, and treatment outcome. For example, the association of rs3742106 (4131 T ! G) with increased plasma tenofovir concentration is observed in HIV-infected patients [78]. rs3765534 (E757K) is associated with a higher incidence of hematopoietic toxicity caused by thiopurine (an effective immuno-suppressant and anticancer agent) [73, 77].

8.2.3

BCRP/ABCG2

Human ABCG2 gene was first isolated from a doxorubicin-resistant breast cancer cell line (MCF-7/AdrVp), thus is also called BCRP (breast cancer resistance protein)

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gene [79–81]. BCRP has one NBD and one TMD (consisting of six transmembrane segments). It is regarded as an ABC half transporter, and a homodimer is required for proper function [82, 83]. BCRP can confer cell resistance to chemotherapeutic drugs (e.g., daunorubicin, doxorubicin, and mitoxantrone) by promoting efflux of drugs out of cells [79, 84]. BCRP is mainly expressed in the liver, intestine, kidney, and brain [85–88]. In addition, it is distributed in colonic epidermis, placenta, and mammary gland [86, 88–90]. Considering its localization in the apical membrane of enterocytes and in the canalicular membrane of hepatocytes, BCRP is thought to facilitate hepatobiliary excretion and to limit oral bioavailability of drugs. This notion is supported by functional assessments (via genetic deletion or chemical inhibition) using animal models and by pharmacogenetic studies in humans. Jonker et al found that elacridar (a dual P-gp/BCRP inhibitor) increases intestinal absorption and reduces hepatobiliary excretion of topotecan, resulting in an increased oral bioavailability of topotecan in Mdr1a/Mdr1b/ mice [91]. Similarly, oral bioavailability of topotecan is significantly increased after co-administration with the highly efficient BCRP inhibitor Ko143 [92]. Additionally, studies with Abcg2/ mouse model support the role of BCRP in intestinal absorption of drugs such as topotecan, sulfasalazine, and antibiotics [93–96]. Sequencing of ABCG2 gene from human samples reveals over 80 naturally occurring variations [97–106]. Some of these ABCG2 variants are associated with increased drug exposure and exacerbated drug-induced toxicity [107]. Notably, the 421 C > A SNP (rs2231142, Q141K) is of the most importance and has been extensively studied. This SNP commonly exists in Asian populations with reported allelic frequencies between 27% and 34% [101, 102, 108]. The Q141K mutation leads to decreased BCRP expression and activity [101, 104, 105, 109]. It is associated with a change in the stability of BCRP protein and an alteration in substrate specificity [110, 111]. In addition, this variant has been recently identified as a risk factor for gout, supporting the notion that BCRP is involved in the elimination of endogenous uric acid [112, 113].

8.2.4

BSEP/ABCB11

The bile salt export pump (BSEP) encoded by ABCB11 gene is localized in the canalicular membrane of hepatocytes [114, 115]. It is a glycoprotein with four putative N-linked glycosylation sites and a molecular weight of 140–170 kDa [114, 116–118]. The protein structure of BSEP is predicted to be highly similar to that of P-gp, although the crystal structure of BSEP has not yet been resolved [117, 118]. BSEP mediates the excretion of conjugated/unconjugated bile salts into the canalicular space [114, 119]. The key role of BSEP in bile salt secretion is highlighted in patients carrying BSEP mutations who have reduced primary bile salts in the bile ( ZT10) and toxicity (ZT2 > ZT10) of the cardiac glycoside oleandrin (a P-gp substrate) [139]. Rhythmicity in P-gp expression is isoform- and gender-dependent. Filipski et al reported that Abcb1b mRNA shows a three-fold daily changes (ZT15 > ZT3) in the ileum mucosa of female B6D2F1 mice, while Abcb1a mRNA does not change with time of the day [141]. In B6D2F1 mice, dosing of the P-gp substrate irinotecan at ZT15 is less toxic than dosing at ZT3. In another study, diurnal variations in Abcb1a/ b mRNA (peak at ZT9 ~ ZT12) and P-gp protein (peak at ZT15) are seen in the ileum

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mucosa of B6D2F1 mice [142]. The levels of P-gp protein are also rhythmic in the colon mucosa and liver of female mice, but not in male mice [142]. Daily fluctuations in intestinal P-gp expression and activity determine intestinal absorption and pharmacokinetics of drug substrates in rats. Abcb1a mRNA shows a significant daily rhythm with a peak at the light-dark transition (ZT12) in the intestine of male Wistar rats [143]. This is associated with the lower absorption of digoxin in the dark phase (ZT12/ZT18 < ZT0/ZT6) [143]. Likewise, Abcb1a mRNA shows a robust rhythm (5.4-fold change) in jejunum of male Sprague-Dawley rats, with higher levels in the daytime (peaking at ZT6) and lower levels at night [144]. By contrast, no temporal difference in intestinal Abcb4 mRNA is observed in Sprague-Dawley rats [144]. Okyar et al revealed that intestinal permeabilities of talinolol and losartan (two P-gp substrates) are smaller in in situ intestinal perfusion studies performed during the night, indicating that P-gp-dependent intestinal excretion is greater during the nighttime (active) than daytime (rest) period in rats [145]. Consistently, in vivo exposure of talinolol is higher after oral administration in the daytime than at night (AUCdaytime > AUCnight) [145]. The inhibitory effects of vinblastine and PSC833 (two P-gp inhibitors) on excretion of talinolol and losartan are stronger for nighttime perfusion [145]. In cynomolgus monkeys (diurnal animals), the expression and activity of P-gp also oscillate in a circadian time-dependent manner [146]. The Abcb1 mRNA significantly oscillates in both intestinal epithelial cells (highest at 09:00 AM and lowest at 15:00 PM) and liver (highest at 03:00 AM and lowest at 21:00 PM) in monkeys, with higher amplitude in the intestine cells than in the liver [146]. P-gp protein in monkey liver is grossly constant throughout the day. By contrast, intestinal P-gp protein shows an obvious circadian rhythm, with low levels in the early light phase (09:00 AM) and higher levels from the midnight phase (15:00 PM) to the early dark phase (21:00 PM) [146]. Accordingly, the Cmax and AUC values of quinidine and etoposide (two P-gp substrates) after oral administration at 09:00 AM (lower intestinal P-gp protein level) are higher than dosing at 21:00 PM (higher intestinal P-gp protein level). However, there is no significant dosing time-dependent variation in the plasma exposure of acetaminophen (a non-P-gp substrate). These findings indicate that circadian expression and activity of P-gp in the intestine influence intestinal absorption and pharmacokinetics of drug substrates in cynomolgus monkeys. P-gp-mediated drug disposition also displays diurnal rhythm in the brain. Kervezee et al determined the exposure levels of intravenous quinidine in the plasma and brain tissue in rats at different times of the day [147]. They found that quinidine exposure in brain tissue varies according to the time of administration (ZT0 ~ ZT8 > ZT12 ~ ZT20) [147]. However, this time difference is lost upon P-gp inhibition by tariquidar (a selective P-gp inhibitor) [147]. By using a radiolabeled P-gp substrate [18F]MC225, Savolainen et al confirmed that P-gp activity displays a daily rhythm in rat brain, with a lower activity at the beginning of the dark period (ZT15) [148]. Contrasting with the finding from Ando et al [140] that mouse Abcb4 is not a circadian gene, Kotaka et al found that Abcb4 mRNA varies with times of the day in

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mouse liver [149]. In the latter study, hepatic Abcb4 mRNA shows a ~ two-fold oscillation, with a trough value at nighttime (ZT16 ~ ZT20). In zebrafish, Abcb4 mRNA oscillates significantly in the liver, with a higher level at the beginning of the light phase (ZT2) and a lower level at the end of light period (ZT10) [150]. However, the rhythms of hepatic ABCB4 protein and its transport activity were not examined in these studies. Therefore, temporal expression of Abcb4 and its contribution to circadian hepatobiliary transport of drugs warrant further investigations.

8.3.2

MRPs

The diurnal expression of MRP2/ABCC2 was first found in the liver of C57BL/6 J mice under constant darkness by using microarrays [151]. Later on, Ando et al found that Abcc2 transcript significantly cycles (> three-fold) in the intestine of C57BL/6 J mice, with a peak level at ZT8 [140]. In addition, they observed a weak fluctuation (< two-fold, with a peak level at ZT12) in Abcc2 mRNA in mouse liver and kidney. MRP2 protein increases in the dark period and decreases in the light period in mouse liver [152]. Accordingly, hepatobiliary excretion of phenolsulfonphthalein (a model substrate of MRP2) is greater when dosing at the beginning of dark phase (ZT12) than at the beginning of light phase (ZT0), resulting in dosing time-dependent exposure (plasma concentration: ZT0 > ZT12) in mice [152]. In the recent study of Yu et al, circadian expression of intestinal MRP2 determines the chronotoxicity of methotrexate in mice [153]. Mice are more sensitive to oral methotrexate dosed at the early dark phase (ZT14) than drug dosed at the early light phase (ZT2) [153]. A higher level of toxicity at ZT14 is associated with a lower MRP2 expression (and a higher drug absorption) and a lower level of toxicity at ZT2 with a higher MRP2 expression (and a lower drug absorption) [153]. Mrp2 mRNA shows a moderate rhythm (a 2.5-fold change) in rat jejunum, with higher levels between ZT6 and ZT12 and lower levels between ZT15 and ZT3 [144]. Iwasaki et al reported that MRP2 protein is slightly fluctuated in the liver in cynomolgus monkeys, with a higher level in the early light phase (09:00 AM) [146]. By contrast, monkey intestinal MRP2 displays an obvious circadian oscillation, with higher protein levels in the nighttime (highest at 21:00 PM) than in the daytime [146]. However, whether rhythmic MRP2 contributes to time-varying disposition of drugs in vivo in monkeys remains unknown. Except for MRP2, little is known about the diurnal rhythmicities in the expression and activity of other MRP members. In mouse liver, Mrp1. Mrp3, and Mrp4 mRNAs show no diurnal rhythms [154]. Stearns et al found that Mrp1 and Mrp3 mRNAs do not display rhythms in rat jejunum [144]. Based on these observations, rodent Mrp1, 3, 4 genes may be not rhythmically expressed in the liver or the intestine. Nonetheless, Kato et al. recently found that MRP4 is rhythmically expressed in mouse bone marrow cells with higher protein levels in the dark period [155]. Diurnal fluctuations in the expression level and activity of MRP4 protein (ZT6 < ZT18) lead to timevarying accumulation of oxaliplatin in bone marrow cells (ZT6 > ZT18), and thus

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are associated with the dosing time dependent changes in the oxaliplatin-induced myelotoxicity (ZT6 > ZT18) [155].

8.3.3

BCRP

BCRP is rhythmically expressed in mouse liver, small intestine, and kidney [156, 157]. The mRNA levels of Abcg2 (isoform B) in these tissues display significant 24-h oscillations, with a peak occurring in the light phase (between ZT6 and ZT10) [157]. The protein level of BCRP in small intestine rises significantly at ZT6, peaks at ZT14, and drops to near basal level by ZT22 [157]. By contrast, BCRP protein does not vary with the circadian time in the livers of C57/BL6 mice [152]. Interestingly, the pharmacokinetic behavior of oral sulfasalazine (a BCRP substrate) is significantly influenced by dosing time (drug exposure: ZT2 > ZT14) [157]. This is potentially attributed to time-dependent BCRP expression and activity in the intestine (i.e., higher BCRP expression leads to a lower absorption of sulfasalazine at ZT14). Also, sulfasalazine accumulation in small intestine depends on dosing time, and the extent of accumulation is inversely correlated with intestinal BCRP protein level [157]. Rhythmic expression of BCRP is also seen in other animal species. In rat jejunum, Bcrp mRNA mildly varies (1.6-fold) with the circadian time [144]. In zebrafish, hepatic Abcg2 mRNA varies with times of the day, with higher levels in the dark phase (highest at ZT18) than in the light phase [150]. In cynomolgus monkeys, BCRP protein shows an obvious circadian oscillation in the small intestine. BCRP protein level is high from the late light phase (15:00 PM) to the early dark phase (21:00 PM), and is very low at other times of the day [146]. By contrast, BCRP protein is not rhythmic, but exhibits a large inter-individual variation in the liver of monkeys [146].

8.3.4

BSEP

BSEP is cyclically expressed in rodent livers [158–161]. Its expression is higher in the early light phase (ZT2 ~ ZT6) in mice [159–161]. It should be noted that the bile acid content and composition diurnally fluctuate in plasma and liver [160, 161]. This may be partly due to the rhythmic efflux activity of BSEP. Additional driving forces of daily oscillation of bile acids are other rhythmic bile acid transporters (e.g., NTCP, ASBT, and OSTα) and biosynthetic enzymes (e.g., CYP7A1, CYP8B1, CYP27A1) [162].

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MATEs

Mate1 mRNA shows a mild rhythm in the liver. Zhang et al observed a 1.3-fold diurnal variation in Slc47a1 transcript in mouse liver, with a trough level at ZT9 [156]. Similarly, Henriksson et al found that MATE1 is diurnally expressed in mouse liver with higher levels at night [163]. By contrast, Mate1 mRNA in the kidney of mice does not exhibit time-dependent oscillation, indicating renal Mate1 is not a circadian gene [164]. To date, nothing is known about circadian expression of MATE2-K transporter.

8.4

Regulation of Efflux Transporters by Circadian Clock

At the molecular level, circadian clock system is composed of several transcriptional-translational feedback loops, in which transcriptional activators [e.g., circadian locomotor output cycles kaput (CLOCK), brain and muscle Arntllike protein 1 (BMAL1), and RAR related orphan receptors (RORs)] and repressors [e.g., period (PER), and REV-ERBα] play significant roles [165, 166]. In addition to core clock components, clock-output genes such as E4 promoter binding protein-4 (E4BP4), proline- and acid-rich basic leucine zipper (PAR bZIP) factors [D-site binding protein (DBP), hepatic leukemia factor (HLF) and thyrotroph embryonic factor (TEF)], and nuclear receptors [e.g., farnesoid X receptor (FXR)] are also sources of diurnal rhythmicity in gene expression [167–170]. Generally, the clock components participate in circadian regulation by directly binding to their respective DNA cis-element such as E-box (for CLOCK and BMAL1), D-box (for E4BP4 and PAR bZIP proteins) or RevRE (for REV-ERBα/β and RORα/β/γ), thus activating or suppressing gene transcription [136]. It has been found that the gene promoter regions of many efflux transporters contain one or more functional element (s) recognized by the clock components, resulting in diurnal expression of these efflux transporters. This part focuses on the molecular mechanisms for circadian regulation of efflux transporters.

8.4.1

P-gp

Several components of circadian clock act to control the 24-h rhythmicity in Abcb1a gene expression. Murakami et al demonstrated that HLF and E4BP4 consist of a reciprocating mechanism in regulating the daily oscillation of Abcb1a transcript [171]. The rhythmic pattern of Abcb1a mRNA in mouse intestine is in phase with that of HLF protein, but antiphase to that of E4BP4 protein [171]. HLF activates, whereas E4BP4 suppresses, the transcription of Abcb1a gene [171]. HLF and E4BP4 regulate Abcb1a transcription by competitively binding to the same PAR bZIP

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BMAL1

REV-ERBα?

CLOCK

D-box

P-gp/Abcb1a

-150GTTTCGCAAT-141

(mouse) -1628TTATGCAA-1621

˄monkey˅ Fig. 8.2 Molecular mechanisms for diurnal rhythmicity in P-gp/Abcb1a expression

response element (150 ~ 141 bp, GTTTCGCAAT) in the gene promoter. HLF periodically binds to Abcb1a promoter (ZT10 > ZT22) and dominates Abcb1a expression when HLF protein is abundant in mouse ileum (ZT10) [171]. E4BP4 binding to the Abcb1a promoter also displays circadian variation, with a maximum value at the time corresponding to the trough of Abcb1a mRNA expression (ZT22) [171]. It is most likely that rat PAR bZIP proteins (such as DBP and HLF) and E4BP4 govern circadian expression of Abcb1a mRNA because their expression patterns in rat intestine are similar to those in mouse intestine [143, 171]. PAR bZIP factors and E4BP4 are also involved in regulation of intestinal P-gp expression in cynomolgus monkeys [146]. A consensus D-box element positioned at 1628 ~ 1621 bp (TTATGCAA) in monkey Abcb1 promoter has been identified to be crucial for respective activation and suppression of Abcb1 transcription by PAR bZIP proteins and E4BP4 [146]. In addition, temporal Abcb1 mRNA in the small intestine is positively correlated with the proteins levels of PAR bZIP factors, but reversely correlated with E4BP4 protein level [146]. CLOCK and BMAL1 are another two circadian regulators of intestinal P-gp expression. Deficiency of CLOCK or BMAL1 remarkably reduces the mRNA and protein levels of intestinal P-gp [139, 171]. Additionally, the diurnal rhythmicity in P-gp/Abcb1a expression is completely abolished in the ileum of Clock- or Bmal1knockout mice [139, 171]. Furthermore, Clock/Bmal1 ablation increases the tissue exposure of P-gp substrates (i.e., digoxin and oleandrin) and eliminates the timedependency in intestinal accumulation, thereby altering systemic drug exposure and toxicity [139, 171]. However, Abcb1a gene promoter does not possess any functional consensus binding element (i.e., E-box) for CLOCK/BMAL1 proteins. Mechanistically, CLOCK/BMAL1 heterodimer controls P-gp rhythmicity through up-regulating HLF (an activator of P-gp) and down-regulating E4BP4 (a suppressor of P-gp) [139, 171]. In vitro findings support this mechanism as down-regulation of CLOCK or BMAL1 protein in serum-shocked CT26 cells greatly decreases Abcb1a mRNA and blunts its temporal variation, accompanied by alterations in the expressions of HLF and E4BP4 [139, 171].

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Collectively, the rhythmic expression of P-gp/Abcb1a is directly governed by the clock-output genes HLF and E4BP4 (Fig. 8.2). Circadian clock components CLOCK/BMAL1 and PER1/2 participate in the regulation of P-gp/Abcb1a through regulating the expressions of HLF and E4BP4 (Fig. 8.2). Although contradicting results have been observed in rhythmic expression of Abcb4 gene in mouse liver, strong evidence supports that Abcb4 is regulated by the clock component CLOCK and its output mediators including E4BP4 and PAR bZIP members [149]. Similar to Abcb1a gene, CLOCK/BMAL1 does not act directly on the Abcb4 promoter, but indirectly regulate Abcb4 through the D-box-acting proteins which are direct regulator of Abcb4 transcription. Indeed, a functional D-box (CCAAATATGTAACTAC) has been identified in Abcb4 promoter, and all PAR bZIP factors (i.e., DBP, TEF and HLF) stimulate, whereas E4BP4 inhibits, Abcb4 transcription via competitive binding to this D-box element [149].

8.4.2

MRPs

BMAL1 and CLOCK have been reported to regulate diurnal expression of MRP2 in mouse liver and intestine. Loss of Bmal1 or Clock decreases MRP2 expression and blunts the rhythmicity, leading to increased sensitivity of mice to toxicity induced by bilirubin and methotrexate [153, 154]. CLOCK/BMAL1 activates Mrp2 transcription by directly up-regulating DBP (an MRP2 activator) expression, and by indirectly down-regulating E4BP4 (an MRP2 repressor) expression via REV-ERBα (an E4BP4 repressor) (Fig. 8.3) [153]. Notably, these transcriptional regulators show robust circadian oscillations in mouse liver and intestine that are positively (for BMAL1, DBP, and REV-ERBα) or negatively (for E4BP4) correlated with the diurnal expression of Mrp2 [152, 153]. Additionally, double knockout of Per1 and Per2 significantly increases the expression level of MRP2 [152, 160]. This is probably due to their antagonistic role in the activation of Mrp2 transcription by CLOCK/BMAL1 (Fig. 8.3).

BMAL1 CLOCK

D-box

Mrp2/Abcc2

-100GATGACATAGCA-89

(mouse) Fig. 8.3 Molecular mechanisms for diurnal rhythmicity in MRP2 expression

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The clock-controlled gene ATF4 (activating transcription factor 4) is a potential regulator of human MRP2. MRP2 expression is significantly up-regulated in ATF4overexpressing human cancer cells [172]. However, no ATF4-binding site (or CRE element) is found in the promoter region of MRP2 gene, suggesting that human MRP2 is not a direct target of ATF4 [172]. Consistent with the observation that rodent Mrp1, Mrp3, and Mrp4 are not cycling genes in mouse liver/intestine, these Mrp genes are not regulated by the core circadian clock components. The expression level and temporal pattern of Mrp3 mRNA show no differences in the liver between Bmal1-deficient and wild-type mice [154]. Specific ablation of Bmal1 in mouse intestine does not alter the expression level of intestinal Mrp1 and Mrp3 [153]. In addition, double knockout of Per1 and Per2 has no effect on Mrp4 expression in mouse liver [160].

8.4.3

BCRP

CLOCK has been identified as a regulator of circadian expression of intestinal BCRP. Clock deficiency reduces the levels of BCRP mRNA and protein, and abolishes their rhythms in mouse small intestine. In addition, temporal accumulation of the BCRP substrate sulfasalazine in mouse intestine is abolished in Clockknockout mice [157]. Mechanistic studies reveal that CLOCK regulates BCRP through ATF4 (a target gene of CLOCK) which periodically binds to Bcrp promoter and activates gene transcription (Fig. 8.4) [157]. Clock ablation decreases ATF4 expression and abolishes its rhythmicity in binding to the Bcrp promoter. In addition, overexpression of ATF4 increases the level of Bcrp mRNA in aMoS7 cells, while overexpression of the clock components (e.g., CLOCK/BMAL1, PER2, CRY1, RORα, and REV-ERBα) or clock-output genes (e.g., HLF and E4BP4) has no effect on Abcg2 expression [157]. Down-regulation of ATF4 reduces the level of Bcrp mRNA, and blunts its rhythm in serum-shocked aMoS7 cells [157]. ATF4 regulates the rhythmic expression of its target genes through the cAMP response element (CRE) [173]. A CRE located at 55 ~ 48 bp (TGACGTCA) of mouse Abcg2 gene (isoform B) promoter is responsible for ATF4 action, as mutation of this site significantly attenuates transcriptional activation of Abcg2 by ATF4 [157]. However, none of the other three clock-acting cis-elements (i.e., E-box, D-box, and RORE/ RevRE) is identified within 3000 bp of the 50 -flanking region of Abcg2 gene Fig. 8.4 Molecular mechanisms for diurnal rhythmicity in BCRP expression

BMAL1 CLOCK

ATF4

CRE -55TGACGTCA-48

(mouse)

Bcrp/Abcg2 (isoform B)

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(isoform B). Therefore, the CLOCK-ATF4 pathway is a main determinant of diurnal expression of BCRP in mouse intestine.

8.4.4

BSEP

Little is known about the role of circadian clock components in regulating the diurnal expression of BSEP. Loss of Npas2 (neuronal PAS domain protein 2) alters the level of Abcb11 transcript in mouse liver [174]. By contrast, Rev-erbα deficiency does not change the level of Bsep mRNA [175]. BSEP is tightly regulated by the bile acid receptor FXR in both humans and rodents [176, 177]. This is confirmed by Fxr/ mice which show markedly reduced basal expression of BSEP along with a complete lack of BSEP induction by bile acids [177]. Deletion of Fxr reduces Bsep mRNA and abolishes its circadian rhythmicity, suggesting that FXR contributes to diurnal expression of hepatic BSEP [160].

8.4.5

MATEs

MATE1 is a potential target of multiple clock components, including CLOCK, BMAL1, and CRY1/2. Liver-specific Bmal1 knockout in mice significantly decreases the levels of hepatic Mate1 mRNA at ZT7 and ZT19 [163]. Likewise, the mRNA level of renal Mate1 is reduced in Clock-mutated mice as compared to wild-type mice [164]. Thus, it is likely that CLOCK/BAML1 could directly regulate the transcription and expression of mouse Mate1. In addition, CRY1 and CRY2 may bind to the promoter region of Mate1 gene in mouse liver [178]. However, the precise mechanisms for circadian clock regulation of MATEs remain to be elucidated.

8.5

Concluding Remarks

The expression and activity of efflux transporters such as P-gp, MRP2, and BCRP oscillate according to time of the day in multiple barrier tissues. Particularly, these efflux transporters show more robust circadian rhythms in the intestine as compared to other tissues such as the liver and brain. This is probably because the gastrointestinal tract is the body’s first line of defense against xenobiotic threats which vary with time of the day. In general, the expression of efflux transporters increases starting from the end of light period (i.e., rest phase for rodents) and reaches the highest level in the early dark phase (i.e., active phase for rodents) in rodent intestine. Accordingly, substrate drugs administered at the times when the abundance of efflux

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transporters is low tend to result in higher drug absorption and bioavailability due to reduced transporter-mediated excretion. Current circadian data on efflux transporters are mainly derived from rodents (nocturnal species). However, it is also noted that efflux transporters are rhythmically expressed in diurnal animals such as monkeys. The protein levels of efflux transporters (i.e., P-gp. MRP2, and BCRP) show significant circadian rhythms (with highest levels at about 21:00 PM) in monkey intestine, but no or weak rhythms in monkey liver. Surprisingly, the circadian patterns of these transporters are similar (peaking in early dark phase) between rodents and monkeys. The circadian patterns in monkeys may contradict with the notion that efflux transporters should be expressed at higher levels in the active phase (with a greater chance for xenobiotic challenge). Circadian expression of efflux transporters are generated and maintained by circadian regulators such as CLOCK, BMAL1, E4BP4, and PAR bZIP proteins. These transcriptional regulators are highly conserved between humans and animals. Thus, it is very likely that efflux transporters are also regulated by circadian clock in humans. Dosing time-dependent pharmacokinetics and pharmacodynamics have been frequently observed for clinical drugs including stains and anticancer agents. However, the precise mechanisms for these circadian events are largely unknown. Whether and how the circadian clock system regulates efflux transporters and chronopharmacodynamics in humans warrant further investigations.

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Chapter 9

Role of Pharmacokinetics in Chronotherapeutics Danyi Lu, Yi Wang, Menglin Chen, Huan Zhao, and Dong Dong

Abstract Life on Earth is dictated by circadian changes (e.g., sunlight, temperature, and humidity) in the environment caused by the planet’s rotation around its own axis. All forms of life have evolved circadian clock system to adapt daily environmental changes. This adaptation results in circadian rhythms (a ~24-h oscillation) in many physiological and behavioral processes. The pharmacokinetics and pharmacodynamics of drugs are influenced by daily fluctuations in physiological processes. Chronopharmacokinetics, a subbranch of chronopharmacology, studies circadian variations in the pharmacokinetic processes (i.e., absorption, disposition, metabolism, and excretion) of drugs. Understanding of the contribution of chronopharmacokinetics to dosing time-dependent drug effects is highly relevant for chronotherapeutics. In this chapter, we perform a review on the influences of circadian rhythms on drug pharmacokinetics in both humans and experimental animals. We also discuss the role of pharmacokinetics in chronotherapeutics. Keywords Chronopharmacokinetics · Chronotherapeutics · Circadian rhythm · Chronopharmaceutical drug delivery system

9.1

Introduction

Circadian rhythms are approximately 24-h biological cycles that function to prepare organisms for daily environmental changes. They are driven by the circadian clock, which is present in virtually all cells of an organism. In mammals, the central clock (also called master clock) is located in the suprachiasmatic nucleus of the

D. Lu · Y. Wang · M. Chen · H. Zhao Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China D. Dong (*) School of Medicine, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_9

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hypothalamus [1, 2]. Clocks presented in other tissues and organs are called peripheral clocks. Although the master clock coordinates peripheral clocks through hormonal (e.g., glucocorticoids) and neural signals, peripheral clocks may be selfsustained [3]. Accumulating evidence supports that pharmacokinetic processes (absorption, distribution, metabolism, and elimination) of many drugs are under the control of circadian clock in animals and humans [4, 5]. Circadian variations in drug pharmacokinetics are usually attributed to diurnal abundance of drug-metabolizing enzymes and/or transporters [6]. Regulation of drug pharmacokinetics by the circadian timing system provides the molecular basis for dosing time dependence of drug efficacy and toxicity. In turn, this knowledge can be used to improve therapeutic outcomes via a chronotherapeutic approach. In this chapter, we perform a review on the influences of circadian rhythms on drug pharmacokinetics in both humans and experimental animals. We also discuss the role of pharmacokinetics in chronotherapeutics.

9.2

Molecular Basis of Circadian Rhythms

At the molecular level, all circadian clocks are composed of a network of transcriptional activators and repressors that form three interlocked autoregulatory feedback loops (Fig. 9.1) [7, 8]. In the main loop, BMAL1 (brain and muscle Arnt-like protein 1) heterodimerizes with CLOCK (circadian locomoter output cycles kaput) or NPAS2 (neuronal PAS domain protein 2) and binds to E-box elements in promoter regions to activate the transcription of clock-controlled genes (CCGs) including PER (period) and CRY (crytochrome). Once accumulating to a high level, CRY and PER proteins in turn downregulate the expressions of CCGs by inhibiting the activity of BMAL1/CLOCK (NPAS2) complex [7, 8]. When the levels of PER and CRY proteins are reduced due to protein degradation, PER and CRY are dissociated from the BMAL1/CLOCK (NPAS2) complex and a new cycle of transcription is started [7, 8]. The second loop is driven by RAR-related orphan receptors (RORα, β, γ) and REV-ERBα/β, which are the target genes of BMAL1/CLOCK [9]. RORs activate, whereas REV-ERBs repress, the transcription of BMAL1 by binding to a specific DNA element RORE (ROR response element) [10]. The third loop involves the transcriptional activator DBP (albumin D site-binding protein) and repressor E4BP4 (E4-binding protein 4). These two factors coordinately regulate the expressions of genes including PER via actions on the D-box cis-element [11].

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PER

CLOCK

BMAL1

CRY

E-box

Cry CCGs

Per

Per

D-box

Dbp Rev-erb

Ror ROR

E4bp4

Bmal1

DBP

E4BP4

REV-ERB

RORE

Fig. 9.1 Transcriptional–translational feedback loops of circadian clock. The circadian clock system consists of three interlocked feedback loops that drive the diurnal expression of clockcontrolled genes (CCGs) via various activators (BMAL1/CLOCK, ROR and DBP) and repressors (PER/CRY, REV-ERB and E4BP4)

9.3

Chronopharmacokinetics: Pharmacokinetic Outcome of Circadian Rhythms

Pharmacokinetic behavior depends not only on the physicochemical characteristics of the drug including chemical structure, molecular weight, ionization state, and hydro-/lipo-solubility but also on the physiological factors such as drugmetabolizing enzymes and transporters in the gastrointestinal tract, liver, and kidney. The physiological parameters may change over the course of the day, resulting in a circadian rhythm in drug disposition and pharmacokinetics. Chronopharmacokinetics investigates circadian oscillations in the in vivo processes (i.e., absorption, distribution, metabolism, and excretion) and pharmacokinetic parameters of drugs [5, 12]. Chronopharmacokinetic studies in humans and other species have shown that dosing time is a key determinant for the pharmacokinetics of many drugs [12].

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Clinical Evidence

Chronopharmacokinetic studies in humans have shown that the pharmacokinetics of over 55 drugs is circadian time dependent (Table 9.1). For some oral medications (e.g., acetaminophen, ketoprofen, mycophenolic acid, nizatidine, prednisolone, tacrolimus, theophylline, valproate, and verapamil), morning dosing results in rapid and sufficient absorption while evening dosing leads to delayed and attenuated absorption. Conversely, other drugs (e.g., amlodipine, cephalexin, ketorolac, mercaptopurine, and pranlukast) are more extensively absorbed when orally administered in the nighttime. However, the exact mechanisms underlying these circadian events are not completely known. For drugs administered via intravenous injection, evening dosing results in lower clearance and thus higher exposure in most cases. It is noted that there are conflicting findings from chronopharmacokinetic studies. For example, two studies found that gentamicin (an aminoglycoside antibiotic) has a higher AUC value after intravenous administration in the evening than in the morning, whereas the other three studies reported no significant differences between daytime and nighttime administration (Table 9.1). In addition, chronopharmacokinetics is influenced by administration route and dosage form, as revealed from the studies of indomethacin and valproate, in which pharmacokinetics displays circadian variations when drugs are administered via oral route, but no circadian variations when drugs are administered via rectal route. Therefore, apart from the physiological rhythms, the physicochemical properties of drugs also determine circadian variations in pharmacokinetic behaviors.

9.3.2

Evidence from Experimental Animals

Various types of experimental animals, including mice, rats, dogs, rabbits, pigs, monkeys, sheep, and cows, have been used to evaluate the effect of dosing time on drug pharmacokinetics. To date, there are more than 80 drugs that show temporal variations in their pharmacokinetic parameters (Table 9.2). In rodents, some drugs (e.g., ampicillin, carbidopa, isoniazid, L-dopa, lithium, and roscovitine) have higher exposure and lower clearance after dosing at the rest period (light phase) compared to the active period (dark phase). By contrast, other drugs (e.g., disopyramide, etidocaine, and gentamicin) have lower exposure and higher clearance when administered at the rest period. In addition to the circadian rhythms in drug absorption, distribution, and renal excretion, diurnal oscillation in drug metabolism is also a determinant of chronopharmacokinetics because the extent of metabolite formation varies according to the circadian time, as demonstrated by the drugs such as aconitine, coumarin, and cyclophosphamide. It is interesting to note that chronopharmacokinetics contributes, at least partly, to dosing time-dependent drug efficacy and toxicity. Higher drug exposure is positively correlated with higher pharmacological effects of many drugs, including aconitine,

Healthy volunteers Healthy volunteers Healthy volunteers Healthy volunteers Hypertensive/normotensive subjects Pregnant and nonpregnant women Healthy volunteers Normocholesterolemic subjects

Healthy volunteers Healthy volunteers

Acetaminophen Acetaminophen Aminophylline Amitriptyline Amlodipine

BMS-181101 Cefalexin

Aspirin Aspirin Atorvastatin

Healthy volunteers

Participants Patients with gynecological malignancies Colorectal cancer patients Subjects with advanced malignancies Patients with esophageal carcinoma Children with acute lymphoblastic leukemia Healthy volunteers Healthy volunteers

Acetaminophen

Acetaminophen Acetaminophen

6-Mercaptopurine

5-Fluorouracil

5-Fluorouracil 5-Fluorouracil

Drug namea 40 epi-adriamycin

Table 9.1 Chronopharmacokinetic studies in humans

po po

po po po

po po iv po po

po

po po

po

iv

iv iv

Dosing routeb iv

07:30, 19:30 08:00, 20:00

08:00, 20:00 06:00, 18:00, 22:00 Morning, evening

08:00, 14:00, 20:00 08:00, 14:00, 20:00 09:00, 21:00 09:00, 21:00 08:00, 20:00

07:30, 13:00, 21:00 08:00, 14:00, 20:00, 02.00 09:00, 21:00

08:00, 20:00

Continuous infusion

Continuous infusion Continuous infusion

Dosing time 07:00, 19:00

No significant differences 06:00: higher bioavailability Morning: higher Cmax and AUC, shorter Tmax 07:30: higher AUC and Cmax 20:00: higher Cmax and longer terminal t1/2

09:00: higher Cmax, AUC and absorption rate constant No significant differences 08:00: more extensive excretion No significant differences 09:00: higher Cmax 20:00: shorter Tmax, higher Cmax

07:30: higher Cmax, lower Tmax and t1/2 No significant differences

No significant differences

16:00: lowest CL Highest concentration at 06:00 and lowest concentration at 15:00 Plasma concentration: 17:00 > 05:00

Pharmacokinetic observationsc 07:00: lower t1/2, higher AUC

(continued)

[29] [30]

[26] [27] [28]

[21] [22] [23] [24] [25]

[20]

[18] [19]

[17]

[16]

[14] [15]

Reference [13]

9 Role of Pharmacokinetics in Chronotherapeutics 191

Cardiac allograft recipients

Healthy volunteers

Healthy volunteers Healthy volunteers

Healthy volunteers Patients with congestive heart failure Healthy volunteers Healthy volunteers

Clavulanic acid Cyclosporine Cyclosporine

Cyclosporine

Dexlansoprazole (MR)

Dextromethamphetamine Diazepam

Diethylcarbamazine Digoxin

Digoxin Diltiazem

Cisplatin

Participants Healthy volunteers Healthy volunteers Patients with organ transplants Healthy volunteers Patients with advanced malignancies Patients with advanced non-small cell lung cancer Healthy volunteers Liver transplant recipients Pancreatic allograft recipients

Drug namea Cefprozil Cephradine Ciclosporin Cilostazol Cisplatin

Table 9.1 (continued)

po po

po po

po po

po

po

po po po

iv

Dosing routeb po po po po iv

08:00, 20:00 06:00, 12:00, 18:00, 24:00

06:00, 18:00 07:00, 16:00

00:00, 08:00, 16:00 Morning, evening 08:00–09:00, 20:00–21:00 08:00–09:00, 20:00–21:00 Breakfast, lunch, dinner or an evening snack 08:40, 20:40 09:00, 13:00, 18:00

06:00, 18:00

Dosing time 12:00, 24:00 09:00, 22:00 h Morning, evening 08:00, 20:00 06:00, 18:00

08:00: shorter Tmax 06:00: lower AUC and Cmax, higher Vd 24:00: lower t1/2

No significant differences 09:00: higher concentration (diazepam and N-desmethyldiazepam) No significant differences 16:00: higher AUC

Lowest Tmax after morning dosing

Morning: higher Cmax

16:00: lower Cmax and AUC Morning: higher concentration 20:00–21:00: higher AUC

18:00: higher clearance

Pharmacokinetic observationsc 24:00: higher AUC 09:00: higher Tmax, t1/2 and AUC Morning: higher Cmax and AUC 08:00: faster absorption rate 18:00: lower AUC

[46] [47]

[44] [45]

[42] [43]

[41]

[40]

[37] [38] [39]

[36]

Reference [31] [32] [33] [34] [35]

192 D. Lu et al.

Patients with percutaneous transhepatic cholangiography with drainage Healthy volunteers Healthy volunteers Healthy volunteers Healthy volunteers Patients with serious infections

Patients with serious infections

Growth hormone deficient patients Healthy volunteers Healthy volunteers

Healthy volunteers

Patients with rheumatoid diseases (n ¼ 16) Healthy volunteers Healthy volunteers

Flomoxef

Folic acid Gentamicin Gentamicin Gentamicin Gentamicin

Gentamicin

Growth hormone

Indomethacin

Indomethacin (PR)

Isepamicin Isosorbide-5-mononitrate

Ibuprofen Indomethacin

Healthy volunteers Breast cancer patients Healthy volunteers

Diltiazem Doxorubicin Fentanyl

im po

po

po per rectum po

iv

iv

po iv iv iv iv

iv

po iv iv

08:00, 20:00 06:30, 18:30

07.00, 11.00, 15.00, 19.00, 23.00 08:00, 12:00, 20:00

08:00, 22:00 09:00, 21:00

08:00, 18:00 09:00, 22:00 08:00, 16:00, 24:00 08:00, 20:00 05:00–12:55, 13:00–20:55, 21:00–04:55 24:00–07:30, 08:00–15:30, 16:00–23:30 Continuous infusion

08:00, 22:00 09:00, 21:00 Continuous infusion/every 4 h/every hour 09:00, 21:00

20:00: slower but more sustained absorption, form more O-desmethyl indomethacin 20:00: higher t1/2 18:30: higher Tmax

No significant differences

Higher at nighttime (23:00–07:00) than during the day (10:00–18:00) 08:00: higher Tmax No significant differences

No significant differences

No significant differences 22:00: lower CL and higher AUC 24:00: lower CL and higher AUC No significant difference No significant differences

21:00: more extensive biliary excretion

08:00: higher AUC 21:00: higher AUC, lower t1/2 and CL No significant differences

(continued)

[63] [64]

[62]

[61]

[59] [60]

[58]

[57]

[52] [53] [54] [55] [56]

[51]

[48] [49] [50]

9 Role of Pharmacokinetics in Chronotherapeutics 193

Healthy volunteers

Patients with Parkinson disease Healthy volunteers

Patients with advanced solid tumors HIV+ subjects Children with acute lymphocytic leukemia Children with standard or highrisk leukemia Children with acute lymphoblastic leukemia Children with leukemia

Ketorolac

Levodopa Levofloxacin

Linifanib

Methotrexate Methotrexate

Methotrexate

Methotrexate

Methotrexate

Osteosarcoma patients Patients with non-Hodgkin’s lymphoma

Healthy volunteers

Ketoprofen

Lopinavir Mercaptopurine

po

Healthy volunteers

iv iv

iv

po

iv

po po

po

po po

po

po

Dosing routeb po

Participants Healthy volunteers

Drug namea Isosorbide-5-mononitrate (SR) Isosorbide-dinitrate

Table 9.1 (continued)

08:00, 20:00 06:00, 18:00

10:00, 21:00

08:00, 20:00

10:00, 21:00

08:00, 19:00 Morning, evening

02:00, 08:00, 14:00, 20:00 07:00, 13:00, 19:00, 01:00 07:00, 13:00, 19:00, 01:00 Daytime, nighttime 02:00, 06:00, 10:00, 14:00, 18:00, 22:00 Morning, evening

Dosing time 08:00, 20:00

21:00: unbound renal clearance decreased significantly 20:00: higher AUC, lower CL No significant differences

21:00: unbound renal clearance decreased significantly No significant differences

No significant difference Evening: higher t1/2 and AUC

Morning: higher Cmax and AUC

Nighttime: slower absorption rate No significant differences

Higher AUC at 02:00/08:00 than at 14:00/ 20:00 07.00: higher Cmax; 01.00: lower absorption rate and CL 19:00/01:00: higher AUC and lower CL

Pharmacokinetic observationsc No significant differences

[74] [75]

[73]

[17]

[72]

[70] [71]

[69]

[67] [68]

[66]

[65]

[64]

Reference [64]

194 D. Lu et al.

Healthy volunteers Cancer patients with severe pain

Kidney transplant recipients Healthy volunteers Healthy volunteers

Healthy volunteers Healthy volunteers and patients with asymptomatic duodenal ulcer disease Healthy volunteers Healthy volunteers

Healthy volunteers

Healthy volunteers Healthy volunteers Healthy volunteers Healthy volunteers

Healthy volunteers

Healthy volunteers

Metronidazole Morphine

Mycophenolic acid Naproxen Nicotine

Nifedipine Nizatidine

Norverapamil Oxprenolol

Pentoxifylline

Pentoxifylline (SR) Phenytoin Pranlukast Prednisolone

Prednisolone

Propranolol

po

po

po po po po

po

po po

po po

po po iv

po po

08:00, 22:00 08:00, 14:00, 20:00, 02:00 01:00, 07:00, 13:00, 19:00 10:00, 22:00 08:00, 20:00 08:00, 20:00 06:00, 12:00, 18:00, 24:00 4-h intervals throughout at least 24 h 02:00, 08:00, 14:00, 20:00

08:00, 19:00 08:00, 22:00

09:00, 21:00 10:00, 22:00 Continuous infusion

07:00, 13:00, 19:00 10:00, 14:00, 18:00

[64]

02:00: lowest AUC and Cmax 08:00: highest AUC and Cmax

(continued)

[89]

08:00: minimum binding 24:00: maximum binding

[85] [86] [87] [88]

[84]

01:00: lower Cmax, higher Tmax and t1/2 10:00: higher AUC and Cmax No significant differences 20:00: higher Tmax, Cmax and AUC 12:00: higher Cmax and AUC values

[82] [83]

[64] [81]

[78] [79] [80]

[76] [77]

22:00: slower absorption rate 14:00: lowest t1/2 02:00: highest t1/2

13:00: lower absorption rate 14:00: lowest Cmax and AUC for morphine and morphine-6-glucuronide 09:00: higher AUC and Cmax, lower Tmax 22:00: higher Tmax Maximum concentrations occur at approximately 11:00, while minimum concentrations occur at 18:00–03:00 08:00: higher AUC and Cmax, lower Tmax 22:00: lower Cmax, longer t1/2, larger Vd

9 Role of Pharmacokinetics in Chronotherapeutics 195

Healthy volunteers Healthy volunteers

HIV+ subjects Healthy volunteers Healthy volunteers Healthy volunteers

Patients with advanced cancer Kidney transplant recipients Kidney transplant recipients Liver transplant recipients Healthy volunteers Breast cancer patients

Colorectal cancer patients Healthy volunteers

Patients with bronchial obstruction Asthmatic children Healthy volunteers

Propiverine Rifampicin

Ritonavir Rosuvastatin Sertraline Sumatriptan

Sunitinib Tacrolimus Tacrolimus Tacrolimus Tacrolimus (MR) Tamoxifen

Tegafur-Uracil Temazepam

Theophylline

Theophylline Theophylline

Participants Hypertensive subjects

Drug namea Propranolol

Table 9.1 (continued)

po po

po

iv po

po po po po po po

po po po po

po po

Dosing routeb po

07:00, 19:00 09:00, 21:00

14:00, 22:00, 06:00

07:00, 19:00 09:00, 22:00

08:00, 13:00, 20:00 09:00, 21:00 08:00, 20:00 08:00, 20:00 08:00, 20:00 08:00, 13:00, 20:00

07:00, 15:00, 23:00 06:00, 12:00, 18:00, 24:00 08:00, 19:00 Morning, evening Morning, evening 07:00, 13:00, 19:00, 01:00

Dosing time 09:00, 21:00

No significant difference No significant differences No significant differences 07:00: highest Cmax and AUC, lowest CL and Vd 19:00: lowest Cmax and AUC, highest CL and Vd 08:00: lower Ctrough No significant differences 08:00: higher Cmax and lower Tmax 08:00: higher Cmax and AUC, lower Tmax No significant differences 08:00: higher Cmax and AUC, lower Tmax, for both tamoxifen and its major metabolites 07:00: higher AUC for 5-Fu and Uracil 22:00: slower absorption rate, lower Cmax, higher t1/2 22:00: smaller AUC due to delayed absorption 07:00: higher AUC due to rapid absorption No significant differences

Pharmacokinetic observationsc 09:00: Propranolol and its metabolites 4-hydroxypropranolol and naphthoxylactic acid have higher Cmax and lower Tmax AUC and Cmax: 07:00 > 15:00 > 23:00 24:00: highest Tmax

[105] [106]

[104]

[102] [103]

[96] [97] [98] [99] [100] [101]

[70] [93] [94] [95]

[91] [92]

Reference [90]

196 D. Lu et al.

iv

iv po po or iv

Patients with serious infections

Patients with serious infections

Children with cystic fibrosis Healthy volunteers Healthy volunteers

Healthy volunteers Epileptic patients Healthy volunteers Healthy volunteers

Healthy volunteers

Healthy volunteers

Tobramycin

Tobramycin

Tobramycin Triazolam Valproate

Valproate Valproate Valproate Valproate

Valproate

Valproate

po

po po po po or per rectum po

iv

po po, iv po

po

Theophylline (SR) Theophylline (SR) Tiracizine

Theophylline (SR)

iv po

Healthy volunteers Patients with reversible airways obstruction Patients with obstructive airways disease Healthy volunteers Healthy volunteers Healthy volunteers

Theophylline Theophylline (SR)

08:30, 20:30

08:00, 20:00

05:00–12:55 , 13:00–20:55, 21:00–04:55 24:00–07:30, 08:00–15:30, 16:00–23:30 08:00, 20:00 07:00, 22:00 06:00, 12:00, 18:00, 24:00 08:00, 20:00 08:00, 20:00 08:00, 20:00 08:30, 20:30

11:00, 23:00 10:00, 22:00 07:00, 19:00

09:00, 21:00

08:00, 20:00 08:00, 20:00

No significant differences No significant differences po: poor absorption at nighttime (18:00 and 24:00); iv: no significant differences 20:00: lower Cmax, higher CL Lower concentration at nighttime 20:00: lower Cmax, higher CL Oral: higher Cmax and lower Tmax in the morning. Rectal administration: no differences Lower renal excretion of Valproate metabolites at nighttime 08:30: higher Cmax and shorter Tmax

No significant differences

11:00: shorter Tmax and higher AUC 22:00: higher t1/2 and lower CL 07:00; lower urinary recovery for tiracizine, higher urinary recovery for the metabolites of tiracizine No significant differences

09:00: higher plasma concentration

08:00: higher elimination rate No significant differences

(continued)

[121]

[120]

[116] [117] [118] [119]

[113] [114] [115]

[57]

[56]

[110] [111] [112]

[109]

[107] [108]

9 Role of Pharmacokinetics in Chronotherapeutics 197

Healthy volunteers Healthy volunteers

Verapamil Zileuton

po po

Dosing routeb po Dosing time 04:00, 08:00, 12:00, 16:00, 20:00 08:00, 22:00 07:00, 11:00 22:00: slower absorption rate No significant differences

Pharmacokinetic observationsc Higher Cmax and AUC at 08:00 and 12:00 [82] [123]

Reference [122]

b

SR, sustained release; MR, modified release; PR, prolonged release iv, intravenous injection; po, per os (oral administration) c AUC, area under the concentration–time curve; Cmax, the maximum plasma concentration; t1/2, terminal half-life; Tmax, time of occurrence of Cmax; Vd, volume of distribution; CL, total body clearance

a

Participants Healthy volunteers

Drug namea Verapamil

Table 9.1 (continued) 198 D. Lu et al.

Mongrel dogs

Domestic shorthair cat Wistar rats

SpragueDawley rats

Wistar rats

Wistar rats

Aminophylline

Aminophylline

Ampicillin

Aspirin

Atenolol

Amitriptyline

ICR mice

New Zealand rabbits Cynomolgus monkeys C57BL/6 mice

Animal model B6D2F1 mice

Amikacin

Aconitine

Acetaminophen

Drug namea (1R,2Rdiaminocyclohexane) oxalatoplatinum(II) Acetaminophen

iv

ig

iv

iv, ig

iv

iv

sc

ip

po

iv

Dosing routeb iv

08:00, 10:00, 12:00, 14:00, 16:00, 20:00 ZT0.5, ZT12.5

ZT0, ZT4, ZT8, ZT12, ZT16, ZT20 12:00, 24:00

ZT0–1, ZT12–13

ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 Continuous infusion

ZT2, ZT14

ZT2, ZT14

ZT1, ZT9, ZT17

Dosing timec ZT8, ZT16, ZT24

Formation of more inactive metabolites at ZT14 Higher CL and lower AUC at ZT10/14 Highest renal CL and lowest serum theophylline concentrations at the beginning of dark phase Higher C0 and lower Vd for theophylline at ZT12–13 Highest AUC and lowest CL at ZT0 Feeding group: higher CL at 24:00; Fasted group: no significant differences Lowest salicylate levels in the blood at 12:00 Higher t1/2 in plasma, heart, muscle, lung, liver, and kidney at ZT0.5

No significant differences

No significant differences

Pharmacokinetic observationsd Higher platinum levels in tissues at ZT8

Table 9.2 Chronopharmacokinetic and chronopharmacodynamic studies in animal models

Maximum analgesic activity at 12:00 /

/

(continued)

[134]

[133]

[132]

[131]

[130]

/ /

[129]

[128]

[127]

Higher toxicity and efficacy at light phase (ZT2/6) /

Higher toxicity at ZT2

[126]

[125]

/e /

Reference [124]

Pharmacological consequence Higher toxicity at ZT7– ZT11

9 Role of Pharmacokinetics in Chronotherapeutics 199

C57BL/6 mice SpragueDawley rats Wistar rats

Wistar rats

Wistar rats

Wistar rats

B6D2F1 mice

Beagle dogs

Wistar rats

SpragueDawley rats Beagle dogs SpragueDawley rats

Brucine Bucinnazine

Capecitabine

Carbamazepine

Carbidopa

Carboplatin

Ceftazidime

Ceftibuten

Ceftriaxone

Cephalexin Cisplatin

Caffeine

Animal model Wistar rats

Drug namea Atenolol

Table 9.2 (continued)

po iv

ip

ii

im

iv

ip

ig

ig

sc

ip ip

Dosing routeb iv

ZT3, ZT9, ZT15, ZT21 ZT2, ZT14 ZT10, ZT22

ZT0, ZT12

ZT0.5, ZT12.5

ZT4, ZT10, ZT16, ZT22 ZT4, ZT10, ZT16, ZT22 ZT0, ZT8, ZT16

ZT5, ZT11, ZT23

ZT2, ZT14

ZT2, ZT14 ZT2, ZT14

Dosing timec ZT0.5, ZT12.5

Higher CL and lower AUC at ZT16 ZT0: highest C0, lowest Vd and MRT; ZT8: highest AUC, t1/2 and MRT, lowest CL Higher absorption rate constant at ZT12.5 Higher Cmax and AUC, lower Tmax at ZT12 ZT9: highest Cmax and AUC, lowest clearance Higher Cmax, lower t1/2 at ZT2 No significant differences

Pharmacokinetic observationsd Shorter elimination half-life in plasma and tissues at ZT12.5 Higher AUC at ZT2 ZT2: higher Cmax and AUC, lower Tmax Higher AUC and lower CL at ZT2 ZT5: highest Cmax and AUC for capecitabine and 50 -deoxy5-fluorocytidine, lowest AUC for 5-fluorouracil and 50 -deoxy-5-fluorouridine Higher AUC and t1/2 at ZT10

/ Higher toxicity at ZT10

/

/

[146] [147]

[145]

[144]

[143]

[142]

/

/

[141]

[140]

[139]

[138]

[136] [137]

Reference [135]

/

/

Higher pharmacological effect at ZT2 /

Pharmacological consequence More pronounced pharmacological effects at ZT12.5 Higher toxicity at ZT2 /

200 D. Lu et al.

New Zealand rabbits ICR mice

Cisplatin

C57BL/6 mice

Wistar rats

Zucker rats

Wistar rats

Wistar rats

Wistar rats

New Zealand rabbits New Zealand rabbits NMRI mice

Donryu rats

Cyclophosphamide

Cyclosporine A

Cyclosporine A

Cyclosporine A

Cyclosporine A

Cyclosporine A

Cyproterone

Disopyramide

Doxorubicin

Cyproterone

Coumarin

Kunming mice C57BL/6 mice

Clofarabine

Cisplatin

BALB/c mice

Cisplatin

ip

ip

iv

iv

ig

ig

ig

iv

iv

ip

ip

ip

iv

iv

ip

ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 ZT4, ZT10, ZT16, ZT22 ZT9, ZT21

ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 ZT1, ZT7, ZT13, ZT19 ZT2, ZT8, ZT14, ZT20 ZT2, ZT14

ZT2, ZT8, ZT14, ZT20 ZT0, ZT12

ZT2, ZT14

ZT2, ZT14

12:00, 00:00

06:00, 12:00, 18:00, 24:00 ZT2, ZT14

04:00, 16:00

Highest AUC and lowest CL and Vd at ZT22 Higher AUC at ZT9

ZT14: higher AUC, Vd, MRT, lower CL Lower AUC at ZT6

Formation of more oxidative coumarin at ZT2 Formation of more active metabolites at ZT2 AUC: ZT8 > ZT14  ZT2 > ZT20 Higher AUC for cyclosporine A and its metabolites at ZT12 Plasma concentration varied largely with the day Higher accumulation in renal tissue at ZT19 Highest Cmax and AUC at ZT2

Cisplatin concentrations in kidney, liver and blood: no significant differences Highest AUC and lowest CL at 24:00 Higher AUC and lower CL at ZT2 No significant differences

(continued)

[163]

[162]

/ Higher toxicity at ZT9

[161]

[160]

[159]

[158]

[157]

[156]

[155]

[153, 154]

[152, 153]

[151]

[150]

[149]

[148]

/

/

Higher nephrotoxicity at ZT12 Higher toxicity at dark period Higher nephrotoxicity at ZT19 /

/

Higher toxicity at ZT2

Higher nephrotoxicity at ZT2 Higher toxicity at 12:00 noon Higher toxicity at ZT2

/

Higher nephrotoxicity at 16:00

9 Role of Pharmacokinetics in Chronotherapeutics 201

Rhesus monkeys NMRI mice

Cynomolgus monkeys Wistar rats

C57BL/6 mice

Wistar rats

ICR mice

BALB/c nude mice SpragueDawley rats Beagle dogs

Ethosuximide

Etoposide

Fuzi (TCM)

Gastrodin

G-CSF

Gefitinib

Gentamicin

Gentamicin

Flomoxef

Etidocaine

Animal model C57BL/6 mice

Drug namea Erlotinib

Table 9.2 (continued)

iv

sc

ig

iv

ig

ig

iv

po

ip

iv

Dosing routeb ig

ZT0, ZT12

ZT1, ZT5, ZT9, ZT13, ZT17, ZT21 ZT2, ZT14

02:00, 08:00, 14:00, 20:00 ZT0, ZT12

ZT10, ZT22

ZT2, ZT14

ZT2, ZT14

ZT4, ZT10, ZT16, ZT22

Dosing timec ZT1, ZT5, ZT9, ZT13, ZT17, ZT21 Continuous infusion

Higher AUC and lower CL at ZT12

Higher plasma concentration at ZT0 Lowest Cmax and AUC values at ZT13 Higher exposure at ZT14

Pharmacokinetic observationsd Lowest Cmax and AUC values at ZT13 Minimal drug levels during 06:00–12:00 Serum: higher Cmax and AUC, lower CL at ZT22; brain: higher AUC at ZT16, higher Cmax at ZT22 Higher intestinal absorption, Cmax and AUC at ZT2 More extensive biliary excretion at ZT2 ZT10: higher systemic exposure of aconitine, hypaconitine and mesaconitine due to lower metabolism Lowest AUC at 02:00

/

Higher toxicity at ZT2

Higher pharmacological effect at ZT0 /

/

Higher toxicity at ZT10

/

/

Higher toxicity at dark period (ZT16/22)

Pharmacological consequence Lowest antitumor activity at ZT13 /

[175]

[173, 174]

[172]

[171]

[170]

[169]

[168]

[126]

[167]

[166]

Reference [164, 165]

202 D. Lu et al.

Wistar rats

SpragueDawley rats SpragueDawley rats

Gentamicin

Gentamicin

Gentamicin

SpragueDawley rats C57BL/6 mice

ICR mice

ICR mice

ICR mice

ICR mice

Wistar rats

Wistar rats

Hypaconitine

IFN-α

IFN-α

IFN-α

IFN-β

Imipenem

Imipramine

Haloperidol

Gentamicin

New Zealand rabbits Wistar rats

Gentamicin

ip, iv

im

iv

iv

iv

sc

ip

ip

ip

ip

im

sc

iv

ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 ZT2, ZT6, ZT10, ZT14, ZT18, ZT22 ZT4, ZT10, ZT16, ZT22 ZT0.5, ZT12.5

ZT2, ZT14

ZT2, ZT14

ZT2, ZT14

ZT9, ZT21

ZT1, ZT7, ZT13, ZT19 ZT8, ZT20 (14 h– 10 h light/dark cycle)

ZT0, ZT6, ZT12, ZT18

ZT4, ZT16

ZT2, ZT15

Higher AUC and lower CL at ZT15 Higher plasma and renal exposure at ZT4 ZT12: highest urinary elimination, lowest concentration in renal cortex Lower renal cortical accumulation during the feeding period Feeding group: higher renal cortical accumulation at ZT8; Fasted group: no significant differences Higher drug levels in serum and brain at ZT9 Higher AUC and lower CL at ZT2 Higher plasma concentration after multiple dosing at ZT2 Higher AUC and lower CL at ZT2 Higher plasma concentration and lower CL at ZT22 and ZT2 Higher plasma concentration at light phase (ZT2 > ZT14) Lowest Cmax and highest Tmax at ZT10 ZT12.5: higher AUC in forebrain for imipramine and its metabolite desipramine /

Higher anti-IFN-α antibody after multiple dosing at ZT2 May have higher antiviral activity at ZT2 May have higher antiviral activity at ZT22 May have higher antiviral activity at ZT18/22 /

Lower toxicity during the feeding period Feeding group: higher nephrotoxicity at ZT8; Fasted group: no significant differences Higher cataleptic response at ZT9 Higher toxicity at ZT2

Severer nephrotoxicity at ZT4 Lowest nephrotoxicity at ZT12

/

(continued)

[188]

[187]

[186]

[185]

[184]

[183]

[182]

[181]

[180]

[179]

[178]

[177]

[176]

9 Role of Pharmacokinetics in Chronotherapeutics 203

Sheep

Rats

Wistar rats

SpragueDawley rats Swiss mice

Wistar rats

C57BL/6 mice

Wistar rats

ICR mice

Indomethacin

Indomethacin

Isepamicin

Isepamicin

L-dopa

Leigongteng (TCM)

Lidocaine

Lithium

Isoniazid

Animal model Wistar rats

Drug namea Imipramine

Table 9.2 (continued)

ip

im

ig

ip

ip

ip

sc

iv

iv

Dosing routeb ip

ZT4, ZT10, ZT16, ZT22 ZT2, ZT6, ZT10, ZT14, ZT18, ZT22

ZT4, ZT10, ZT16, ZT22 ZT2, ZT14

ZT2, ZT8, ZT14, ZT20 ZT1, ZT7, ZT13, ZT19

ZT6, ZT18

08:00, 14:00, 20:00, 02:00 (a natural 10 h–14 h light/dark cycle) ZT2, ZT14, ZT20

Dosing timec ZT1, ZT13

Pharmacokinetic observationsd ZT1: higher plasma concentrations for imipramine and its metabolite desipramine 14:00: highest C0 and AUC, lowest CL and Vd; 02:00: lowest C0 and AUC, highest CL and Vd ZT2: higher Cmax and AUC, lower Vd and CL Plasma/renal drug levels: ZT6 > ZT18 Accumulation in renal cortex: ZT2/8 > ZT14/20 ZT1: highest Cmax and AUC, lowest Vd and CL; ZT7: lowest Cmax and AUC, highest Vd and CL Higher CL and lower AUC at ZT16 ZT2: higher systemic exposure of triptolide due to lower metabolism Highest AUC, lowest t1/2, CL and Vd at ZT10 Highest AUC and lowest CL at ZT2 [197]

[196]

/ Higher toxicity at ZT2

[195]

[141] Higher toxicity at ZT2

/

[193, 194]

[192]

[191]

[191]

/ Nephrotoxicity: ZT6 > ZT18 Nephrotoxicity: ZT2/8 > ZT14/20 Maximum hepatotoxicity at ZT1

[190]

Reference [189]

/

Pharmacological consequence Higher antidepressant activity at ZT1

204 D. Lu et al.

Swiss mice

Swiss mice

ICR mice

SpragueDawley rats

Prim’Holstein cows BALB/c mice

NMRI mice

C57BL/6 mice ICR mice

Wistar rats

ICR mice

Landrace pigs

Loratadine

Lorazepam

Luteolin

Melatonin

Melatonin

Meperidine

Mepivacaine

Methotrexate Methotrexate

Methotrexate

Methotrexate

Methotrexate

iv

ip

iv

ig ip

ip

ip

iv

iv, id

ig

ig

ig

Continuous infusion

ZT4, ZT10, ZT16, ZT22 ZT2, ZT14 ZT0, ZT6, ZT12, ZT18 ZT0, ZT6, ZT12, ZT18 ZT2, ZT6, ZT10, ZT14, ZT18, ZT22

ZT2, ZT14

14:30, 22:30

ZT4, ZT16

ZT0, ZT12

ZT3, ZT15

ZT1, ZT9, ZT17

Higher concentration at early light phase

AUC values are slightly higher at ZT2 and ZT6

Higher AUC at ZT14 Lower AUC and higher CL at ZT0/18 Higher AUC at ZT18

Higher Cmax and AUC for both meperidine and normeperidine at ZT14 Higher Vd and t1/2 at ZT16

ZT9: highest Cmax and AUC for loratadine and its metabolite desloratadine No significant differences in the brain Plasma concentration: ZT12 > ZT0 ZT4: higher AUC for melatonin, lower AUC for melatonin metabolite No significant differences

More severe toxicity (body weight loss and leukopenia) in the late dark period and the early light period (ZT22– ZT6) /

/

[204]

Higher toxicity between ZT10 and ZT16 Higher toxicity at ZT14 Toxicity: ZT6 > ZT18

(continued)

[209]

[208]

[207]

[205] [206]

[203]

[202]

[201]

[200]

[199]

[198]

Stronger analgesic effect at ZT14

/

Severe neurologic deficit at ZT3 Activation of hepatic NRF2 pathway: ZT12 > ZT0 /

/

9 Role of Pharmacokinetics in Chronotherapeutics 205

New Zealand rabbits

B6D2F1 mice

C57BL/6 mice

Beagle dogs Wistar rats

SpragueDawley rats SpragueDawley rats C57BL/6 mice B6D2F1 mice

Midazolam

Mitoxantrone

Morphine

Morphine Mycophenolate mofetil

Nifedipine

Pentazocine Pentobarbital

Oleandrin Oxaliplatin

Beagle dogs Mice

Wistar rats

Metoprolol

Norfloxacin

Animal model Wistar rats

Drug namea Metoprolol

Table 9.2 (continued)

iv ip

ig iv

ip

ig

po ip

ip

iv

iv

iv

Dosing routeb iv

Day, night ZT4, ZT16

ZT3, ZT9, ZT15, ZT21 ZT2, ZT10 ZT0, ZT8, ZT16

ZT0, ZT8, ZT16

07:30, 19:30 ZT1, ZT7, ZT13, ZT19

ZT4, ZT6, ZT10, ZT22 ZT2, ZT14

ZT2, ZT7, ZT11, ZT15

ZT0.5, ZT12.5

Dosing timec ZT0.5, ZT12.5

Formation of more morphine glucuronide at ZT2 Higher AUC and Cmax at 07:30 Lower Cmax and AUC for the active metabolite mycophenolic acid at nighttime (ZT13/19) Plasma and tissue exposures: ZT0 > ZT8 > ZT16 ZT3/9: higher absorption and exposure, lower clearance Higher Cmax and AUC at ZT2 ZT0: highest C0, lowest Vd, t1/2 and MRT; ZT16: lowest C0, highest Vd, t1/2 and MRT Higher Vd and t1/2 at night Potential higher clearance at ZT16

Pharmacokinetic observationsd Higher t1/2 in heart, muscle, liver and kidney at ZT0.5 Shorter elimination half-life in plasma and tissues at ZT12.5 Highest Cmax and AUC for both midazolam and 1-OH midazolam at ZT15 Highest AUC at ZT10

[219] [220]

[218] [142]

Minimal toxicity at ZT10 /

/ Loss of the righting reflex: ZT4 > ZT16

[217]

[216]

[213] [214, 215],

[212]

[211]

[210]

[135]

Reference [134]

/

/

/ Highest hematological toxicity at ZT7

/

Lower toxicity at dark period

More pronounced pharmacological effects at ZT12.5

Pharmacological consequence /

206 D. Lu et al.

Wistar rats

New Zealand rabbits Wistar rats

Wistar rats

SpragueDawley rats

Cynomolgus monkeys B6D2F1 mice

Wistar rats Wistar rats

New Zealand rabbits ICR mice

Std-ddY mice

FVB mice

Hypertensive rats

Procainamide

Propofol

Propranolol

Propranolol

Puerarin

Quinidine

Roscovitine

Sinomenine Sotalol

Sulfamethoxazole

Tacrolimus

Tamoxifen

Temocapril

Sulfasalazine

C57BL/6 mice

Pentoxifylline

ig

ig

ig

ig

ig

iv iv

ig

po

iv

iv

iv

iv

ip

ip

ZT0, ZT4, ZT8, ZT12, ZT16, ZT20 ZT2, ZT14

ZT3, ZT15

ZT2, ZT14

09:00, 22:00

07:00, 19:00 ZT0.5, ZT12.5

ZT3, ZT19

ZT2, ZT14

07:00, 19:00

ZT0.5, ZT12.5

ZT0.5, ZT12.5

ZT4, ZT10, ZT16, ZT22 ZT3, ZT9, ZT15

ZT2, ZT14

No significant differences

Higher intestinal absorption, Cmax and AUC at ZT2 ZT3: higher plasma and tissue exposure, lower clearance Higher Cmax and AUC at 07:00 Higher t1/2 in heart, muscle, lung, liver and kidney at ZT0.5 Higher Cmax, AUC and t1/2, lower CL at 22:00 Higher intestinal absorption, Cmax and AUC at ZT2 Higher Cmax and AUC, lower Tmax at ZT15 Highest AUC at ZT16

Higher t1/2 in plasma, muscle, lung and brain at ZT0.5 Shorter elimination half-life in plasma and tissues at ZT12.5 Higher AUC with evening dosing (19:00)

Formation of more oxidized metabolite at ZT14 Formation of more N-acetylprocainamide at ZT22 CL: ZT9 > ZT15 > ZT3

Higher toxicity at ZT14

/

(continued)

[230]

[101]

[229]

[228]

/ /

[227]

[226] [134]

[225]

[126]

[224]

[135]

[134]

[223]

[222]

[221]

/

/ /

/

More pronounced pharmacological effects at ZT12.5 Better glucose-lowering effects with evening dosing (19:00) /

Sedative effect: ZT9 < ZT15 < ZT3 /

/

/

9 Role of Pharmacokinetics in Chronotherapeutics 207

Domestic shorthair cat Dutch rabbits

SpragueDawley rats

SpragueDawley rats

SpragueDawley rats

Wistar rats

C57BL/6 mice

Theophylline (SR)

Tobramycin

Tobramycin

Tobramycin

Tolbutamide

Triptolide

Timolol

Theophylline

Theophylline

Animal model SpragueDawley rats New Zealand rabbits Wistar rats

Drug namea Tetrabenazine

Table 9.2 (continued)

ip

iv

iv

iv, ip

ip

Ocular absorption, iv

po

iv

ig

Dosing routeb unknown

ZT2, ZT14

ZT8, ZT20 (14 h– 10 h light/dark cycle) Continuous infusion for 6 h (14 h–10 h light/dark cycle) ZT0, ZT8, ZT12

ZT8, ZT20 (14 h– 10 h light/dark cycle)

ZT0, ZT6, ZT12, ZT18

07:00, 19:00 (dark span: 20:30–03:30) ZT0–1, ZT12–13

ZT0, ZT8, ZT16

Dosing timec ZT6, ZT18

Formation of more inactive metabolites at ZT14

No significant differences

Lower accumulation rate when infused at 20:00–02:00

Higher Cmax and AUMC at ZT12–13 Ocular absorption: highest AUC and Cmax at ZT6 in the eye; iv: highest plasma AUC at ZT6 Feeding group: higher exposure in serum and renal cortex at ZT8; Fasted group: no significant differences ZT8: higher AUC and cortical level, lower CL

No significant differences

Pharmacokinetic observationsd No significant differences in the plasma and brain Lowest AUC and t1/2 at ZT16

Hypoglycemic effect: ZT12 > ZT8 > ZT0 Higher toxicity at ZT2

/

Higher nephrotoxicity at ZT8

[127]

[238]

[237]

[236]

[235]

[234]

/

/

[130]

[233]

[232]

Reference [231]

/

/

Pharmacological consequence Higher sedative effect at ZT18 /

208 D. Lu et al.

ICR mice ICR mice ICR mice

Rhesus monkeys Landrace pigs

Valproate Valproate Valproate

Valproate

iv

iv

iv iv ig, iv

ip ip

sc

Continuous infusion

Continuous infusion

Continuous infusion ZT10, ZT18 ZT2, ZT6, ZT10, ZT14, ZT18, ZT22

ZT10, ZT18 ZT1, ZT7, ZT13, ZT19

ZT10, ZT18

Higher concentration at early dark phase

Higher concentration at ~06:00

Highest clearance at ZT14 Higher clearance at ZT18 Higher drug concentrations in the light phase

No significant differences in embryo No significant differences ZT7: lowest Cmax and AUC, highest clearance

/

Higher embryotoxicity at ZT10 Higher toxicity at ZT10 ZT7: highest anticonvulsant efficacy, lowest hepatic and renal toxicities / / Higher toxicity and electroshock seizure threshold in the light phase / [209]

[246]

[244] [244] [245]

[240] [241–243],

[239]

b

SR, sustained release; TCM, traditional Chinese medicine id, intradermal injection; ig, intragastric injection; ii, intraintestinal injection; im, intramuscular injection; ip, intraperitoneal injection; iv, intravenous injection; po, per os (oral administration); sc, subcutaneous injection c ZT, zeitgeber time (ZT0 represents lights on); unless otherwise stated, animals are maintained on a 12 h light and 12 h dark cycle d AUC, area under the concentration–time curve; AUMC, area under the first moment of the concentration–time curve; C0, plasma concentration at time zero; Cmax, the maximum plasma concentration; MRT, mean residence time; t1/2, terminal half-life; Tmax, time of occurrence of Cmax; Vd, volume of distribution; CL, total body clearance e /, not available

a

ICR mice Swiss mice

Valproate Valproate

Vinorelbine

ICR mice

Valproate

9 Role of Pharmacokinetics in Chronotherapeutics 209

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amikacin, caffeine, coumarin, cyclophosphamide, cyclosporine A, doxorubicin, erlotinib, etidocaine, G-CSF, gentamicin, haloperidol, hypaconitine, imipramine, isepamicin, isoniazid, lithium, luteolin, meperidine, methotrexate, mycophenolate, oleandrin, propofol, puerarin, tobramycin, and triptolide (Table 9.2). However, circadian rhythms in drug targets and tissue sensitivity may also have significant contributions because the chronoeffects of some drugs (e.g., aspirin, clofarabine, lorazepam, temocapril, tetrabenazine, and valproate) do not depend on chronopharmacokinetics. For example, lorazepam causes more severe neurologic defect in the light phase than in the dark phase (ZT3 > ZT15) in mice, while the lorazepam levels in the brain are not different between ZT3 and ZT15 dosing.

9.4

Mechanisms of Chronopharmacokinetics

The physiological rhythms in gastrointestinal tract (e.g., gastric pH, motility, emptying time, gastrointestinal blood flow, and transporters), blood circulation system (e.g., binding capacity of plasma proteins and blood flow through an organ), liver (e.g., drug-metabolizing enzymes, transporters, and hepatic flow), and kidney (e.g., renal blood flow, transporters, glomerular filtration, tubular reabsorption, electrolytes, and urinary pH) may contribute to the circadian time-dependent pharmacokinetic behaviors. In this part, the influences of circadian rhythms on drug absorption, distribution, metabolism, and excretion are summarized and discussed.

9.4.1

Circadian Variations in Drug Absorption

Oral administration is the most common means of drug intake due to its simplicity and convenience. Absorption rates of oral drugs can be remarkably influenced by the timing of administration (Tables 9.1 and 9.2). Drug absorption in the gastrointestinal tract is determined by multiple biological factors including gastric pH, gastric emptying, gastrointestinal motility, intestinal mucosa blood flow, drug-metabolizing enzymes, and transporters [247]. All these factors are regulated by the circadian timing system, contributing to dosing time-dependent pharmacokinetic parameters such as Tmax, Cmax, and AUC. Moore et al. reported a circadian rhythm in gastric acid secretion in humans, with a higher rate in the evening than in the morning [248]. Accordingly, the gastric pH, which affects the ionization and hydrophobicity of drugs, presents a strong circadian pattern [248]. In humans, oral drugs are generally absorbed faster during the daytime because of faster gastric emptying and higher rate of gastrointestinal mobility after a daytime meal than a nighttime meal [249, 250]. An increase in gastric emptying time at evening may cause a delay in reaching maximum plasma concentrations (higher Tmax) [249]. For instance, amitriptyline [24], diazepam [251], nifedipine [64, 252], acetaminophen [253], and temazepam [103] demonstrate a faster absorption (with a

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211

lower Tmax value) after morning intake, which is associated with faster gastric emptying in the morning [64]. Drug transporters in the intestine are key regulators of drug absorption and bioavailability [254]. The expression and activity of these transporters in enterocytes display significant circadian rhythms and thus contribute to temporal fluctuations in absorption and pharmacokinetics of many oral drugs [4, 6]. P-gp and BCRP proteins peak in the early dark phase in rodent and monkey intestines [126, 218, 228, 255, 256]. This is associated with poorer absorption and lower plasma exposure of P-gp substrates (e.g., digoxin, oleandrin, quinidine, and etoposide) and BCRP substrates (e.g., sulfasalazine) when dosed in the early nighttime [126, 218, 228, 255, 256]. By contrast, intestinal MRP2 protein shows higher levels in the early light phase (ZT2 > ZT14). Mice are more sensitive to oral methotrexate (an MRP2 substrate) dosed at ZT14 (higher drug absorption) than that dosed at ZT2 (lower drug absorption) [205]. Moreover, the uptake transporter OCTN1 is rhythmically expressed in mouse intestine with the highest protein level at ZT14, leading to time-dependent intestinal accumulation (ZT14 > ZT2) and systemic exposure (ZT14 > ZT2) of gabapentin (an OCTN1 substrate) [257].

9.4.2

Circadian Variations in Drug Distribution

Unlike simple diffusion in an equilibrium dialysis chamber, drug distribution in the body is much more complex and depends on a number of variables that may vary according to time of the day (so-called rhythmic variables) [258]. Rhythmic variables including blood flow, cardiac output, and drug binding (to both plasma and tissues proteins) can affect the body distribution of drugs. After absorption, drug molecule is usually bound with plasma protein, while the unbound drug is distributed to targets in the body to exert pharmacological effects. Interestingly, the drug– protein binding process shows significant circadian rhythms, as exemplified by several drugs (e.g., roscovitine, mycophenolic acid, and valproate) with a high protein binding (>80%) and a small apparent Vd [5, 214]. In addition, the cardiovascular system exhibits higher cardiac output (~30%) and higher blood flow to the extra-splanchnic-renal regions in the morning as compared to the evening [259, 260]. Thus, circadian fluctuations in drug–protein binding and blood flow may partly account for dosing time-dependent pharmacokinetics. Permeability barriers (e.g., blood–brain barrier, blood-placental barrier, and blood-testicular barrier) also have significant influences on in vivo drug distribution. It has been shown that drug permeability through blood–brain barrier varies over circadian time, indicating the functions of blood–brain barrier are controlled by circadian clock [261–263]. The efflux transporter P-gp is highly expressed at blood–brain barrier and governs drug entry into the brain. The expression and activity of P-gp vary according to time of the day, determining the circadian exposure of P-gp substrate (e.g., quinidine) in brain tissue [263].

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Circadian Variations in Drug Metabolism

In mammals, the major site of drug metabolism is the liver, a highly vascularized organ. In general, the extent of hepatic metabolism mainly depends on the catalytic ability of drug-metabolizing enzyme (for drugs with a low extraction ratio) and hepatic blood flow (for drugs with a high extraction ratio). In healthy supine subjects, the highest hepatic blood flow is estimated to occur at 8:00 AM [264]. Since hepatic blood flow changes with time of the day, the extent of hepatic clearance may vary accordingly [80, 264, 265]. The most important enzymes involved in drug metabolism are members from families of cytochromes P450 (CYPs), carboxylesterases (CES), UDP-glucuronosyltransferases (UGTs), and sulfotransferases (SULTs). Many of these enzymes (e.g., CYP3A11, CES1, UGT2Bs, and SULT1A1) show diurnal fluctuations in their expression and activity, thereby contributing to chronopharmacokinetics and chronopharmacodynamics of their substrate drugs [6]. For example, diurnal expression of CYP3A11 in mouse liver is associated with dosing time-dependent pharmacokinetics and toxicity (ZT2 > ZT14) of aconitine [127], hypaconitine [182], triptolide [127, 195], and brucine [136]. Mechanistically, circadian clock components (e.g., CLOCK, BMAL1, DBP, and E4BP4) can directly bind to one or more cis-elements (e.g., E-box and D-box) located in the gene promoter and activate or suppress the transcription of the enzymes [6]. Consistent with the findings from animal studies, a recent study found that multiple human CYP enzymes (i.e., CYP1A2, 2B6, 2C8, 2D6, 2E1, and 3A4) display rhythmic expression in synchronized hepatoma cells [266].

9.4.4

Circadian Variations in Drug Excretion

Most water-soluble drugs and metabolites are eliminated into urine. Glomerular filtration rate (GFR), renal blood flow (RBF), urinary pH, and tubular resorption are variables affecting urinary excretion of drugs. All these variables have been shown to oscillate in a circadian time-dependent manner, with higher values in the daytime in humans [267]. Likewise, GFR and RBF are higher in the active phase than in the rest phase in rodents [268]. As a result, urinary nifedipine excretion is more extensive at the end of the active period than during the inactive period (0.0342% vs. 0.0137%) in rats [216]. Besides, temporal changes in urinary pH modify the ionization and thus chronopharmacokinetics of drugs such as sodium salicylate and sulfasymazine [269–271]. Intriguingly, diurnal expression of renal drug transporters, which facilitate the elimination or reabsorption of polar molecules, may contribute to dosing time-dependent drug elimination and nephrotoxicity. For instance, higher expression of organic cation transporter 2 (OCT2) is responsible for higher renal clearance and nephrotoxicity of cisplatin when administered in the early light phase in mice [150].

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213

Circadian rhythm also affects hepatobiliary excretion of endogenous and exogenous substances including drugs. Excretion of bile acids, lipids, and proteins into the bile shows a strong circadian rhythm, with peak levels at ZT16 and trough levels at ZT4 in rats [272, 273]. In rats and patients receiving percutaneous biliary drainage, biliary excretion of drugs such as ampicillin and flomoxef presents a circadian pattern [51, 168, 274]. One main reason is that the production of bile acids follows a strict diurnal rhythm [275, 276]. This is probably because circadian clock system directly regulates rhythmical expression of cholesterol-7-lipid-hydroxylase (CYP7A1), a rate-limiting enzyme for bile acid synthesis [277–280]. Additionally, biliary transporters (e.g., MRP2) exhibit circadian rhythms, contributing to temporal fluctuation in hepatobiliary excretion of drugs and their metabolites. For example, MRP2 shows higher protein levels in the dark period in mouse liver, resulting in diurnal variations in hepatobiliary excretion (ZT12 > ZT0) and plasma exposure (ZT0 > ZT12) of phenolsulfonphthalein (an MRP2 substrate) in mice [281].

9.5

Pharmacokinetics-Based Chronotherapeutics

Advanced knowledge in chronobiology has greatly facilitated the development of novel drug dosing schedules according to circadian rhythms in drug exposure, drug targets, and/or disease symptoms. So far, there are over 100 clinical trials concerning chronotherapy for the diseases with high prevalence, including hypertension, cancers, asthma, hyperlipidemia, arthritis, and myocardial injury [282]. About 75% of these clinical trials demonstrate dosing time-dependent efficacy or toxicity. It is worth noting that drugs with half-lives of less than 15 h tend to have more pronounced time-varying effects, while longer-acting drugs show no or weak circadian time-dependent effects [282]. This indicates that pharmacokinetics is a key determinant of dosing time-dependent pharmacodynamics. Indeed, as noted in Tables 9.1 and 9.2, the pharmacokinetics of many drugs varies according to time of the day. In this section, we provide some examples that highlight the important role of pharmacokinetics in chronotherapeutics.

9.5.1

Acetaminophen

Acetaminophen (also known as paracetamol) is the most commonly used drug to treat pain and fever [283]. However, it can elicit acute hepatic necrosis in humans and experimental animals [284, 285]. The major cause of this toxicity is CYP-mediated formation of the reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) that is capable of binding to cellular macromolecules [285–289]. Acetaminophen-induced hepatotoxicity is shown to depend on the dosing time in rodents, namely, higher toxicity in the activity phase than in rest phase [290–293]. This is correlated with the circadian rhythms in acetaminophen-metabolizing enzymes (i.e.,

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CYP2E1, CYP3A4, and CYP1A2) [290–294]. These CYP enzymes show higher expression levels and activities in the dark period in mouse liver, leading to increased formation of NAPQI and hepatotoxicity [290–294]. Besides, the temporal variations in hepatic glutathione concentrations (daytime > nighttime) is another factor determining acetaminophen chronotoxicity [290, 295, 296]. However, whether the circadian time can influence the toxicity of acetaminophen in humans has not been studied and is warranted for further investigations.

9.5.2

Cisplatin

Cisplatin is an alkylating agent used to treat a number of cancers [297]. However, its use is limited by severe dose-limiting side effects such as nephrotoxicity [298]. Renal dysfunction induced by cisplatin depends on dosing time in rodents, with more severe toxicity in the light phase than in the dark phase [147, 148, 150, 299]. This may be partly due to lower cisplatin clearance and higher exposure of cisplatin in the light period, which are associated with the circadian variations in GFR (light < dark) and renal OCT2 levels (light > dark) [150]. Likewise, evening dosing of cisplatin has higher clearance and lower side effects (i.e., leucopenia, neutropenia, and gastrointestinal toxicity) in cancer patients [36]. Hence, the toxicity of cisplatin can be reduced by using a chronotherapeutic strategy.

9.5.3

Cyclophosphamide

Cyclophosphamide is widely used to treat various forms of cancers and to suppress the immune system [300, 301]. It is a prodrug and bioactivated by CYP2B6 to 4-hydroxy-cyclophosphamide (the active form) in the liver [302, 303]. Both therapeutic and toxic effects of cyclophosphamide are dependent on the time of drug administration [153, 154, 304–307]. For example, minimal hepatotoxicity is observed when cyclophosphamide is dosed at the light–dark transition than dosed at other times in mice [153, 154]. The chronotoxicity of cyclophosphamide has been shown to be controlled by the core clock components CLOCK and BMAL1 [153, 154]. CLOCK/BMAL1 complex regulates cyclophosphamide metabolism and chronopharmacokinetics through modifying the circadian expression of CYP2B10 (an ortholog of human CYP2B6) in mice [153, 154]. Higher CYP2B10 protein in the early light phase generates more active metabolites, resulting in more severe cyclophosphamide hepatotoxicity in mice [153]. In addition, modification of B cell survival by the circadian timing system may be another factor determining the circadian responses to cyclophosphamide [154]. By taking advantage of temporal variations in metabolism and tolerability to cyclophosphamide, chronotherapy schedules have been shown to improve therapeutic efficacy and decrease side effects [305–307].

9 Role of Pharmacokinetics in Chronotherapeutics

9.5.4

215

Doxorubicin

Doxorubicin (adriamycin) is widely used for the treatment of solid tumors and acute leukemias [308, 309]. However, its use is limited by doxorubicin-induced toxicities such as congestive heart failure, myelosuppression, nausea, and vomiting [309]. These adverse reactions have been reported to be influenced by the dosing time of doxorubicin. For example, the incidence of nausea in the evening dosing is three times higher than morning dosing in breast cancer patients [310]. Doxorubicininduced chronotoxicity is dependent on daily variations in doxorubicin clearance (lower CL at night) and exposure (higher AUC at night) that are mainly associated with circadian change in hepatic blood flow (lower at night) [49]. Consistently, doxorubicin clearance is significantly lower in the rest phase (ZT9) compared with the activity phase (ZT21) in rats, resulting in higher levels of AUC and toxicity [163]. In addition, timed delivery of doxorubicin plus other chemotherapeutic agents (e.g., cisplatin and docetaxel) is effective and well tolerated in cancer patients and human tumor xenograft models [311–313].

9.5.5

Gentamicin

Gentamicin is an aminoglycoside antibiotic used to treat various types of bacterial infections. However, it is also one of the leading causes of drug-induced nephrotoxicity [314, 315]. In rodents, gentamicin exhibits higher antibacterial activity and lower toxicity in the active period than in the rest period [178, 179, 316, 317]. More severe nephrotoxicity in the light phase is correlated with higher accumulation of gentamicin in renal cortex [178–180, 317]. The time of feeding seems to be a more important modulator of dosing time-dependent gentamicin nephrotoxicity than the light–dark cycle, as fasting abolishes the rhythmicity of toxicity [179]. In fact, the GFR is higher during the period of food intake due to increased protein load [55, 318]. An increase in GFR may explain lower accumulation of gentamicin and lower nephrotoxicity when drug is administered in the feeding (dark) period compared with dosing in the fasting (light) period. Likewise, clearance of gentamicin in the midnight is slower than in the daytime in healthy volunteers [53, 54]. Accordingly, it is postulated that gentamicin causes time-dependent nephrotoxicity in humans, namely, higher toxicity at the fast stage and lower toxicity at the feeding stage.

9.5.6

Methotrexate

Methotrexate is a chemotherapeutic agent and immune suppressant used for treatment of cancers, autoimmune diseases, ectopic pregnancy, and for medical abortions

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[319, 320]. Various side effects (e.g., hepatotoxicity and nephrotoxicity) have been reported in patients treating with methotrexate [321]. Higher exposure of intravenous methotrexate has been observed during the rest period due to slower clearance [72–74, 208]. This may be associated with the higher methotrexate toxicity in the early light phase in mice [208]. However, oral methotrexate is more toxic in the early dark period (ZT14 > ZT2) in mice, mainly depending on the circadian rhythm of intestinal MRP2 expression (higher MRP2 level at ZT2 leads to lower absorption and toxicity) [205]. These findings indicate that pharmacokinetics determines the chronotoxicity of methotrexate, which may have implications for chronotherapy with methotrexate. In fact, it has been found that bedtime methotrexate chronotherapy is safer, markedly reducing disease activity and improving the functional capacity of rheumatoid arthritis patients [322].

9.5.7

Morphine

Morphine is one of the most important analgesic drugs used for both acute pain and chronic pain [323, 324]. Morphine is addictive and prone to abuse [325]. Morphine undergoes extensive hepatic metabolism, and 60–80% of morphine is excreted into urine as glucuronide metabolites [326]. The pharmacokinetics of morphine (oral administration) has been shown to be dependent on dosing time in cancer patients with severe pain, with lower plasma levels of morphine and morphine-6-glucuronide for dosing at 14:00 PM compared to dosing at 10:00 AM or 18:00 PM [77]. In mice, the analgesic effect of morphine is better in the late dark phase and early light phase [327]. This is correlated with higher concentrations of morphine and morphine glucuronide in this time period [212, 213].

9.5.8

Theophylline

Theophylline is a bronchodilator used in treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease [328]. CYP-mediated metabolism is the primary pathway for clearance and detoxification of theophylline in humans and rodents [329–331]. In humans, oral intake of theophylline in the morning has higher absorption rate (shorter Tmax) and higher AUC than evening dosing [104, 105, 109, 110]. By contrast, nighttime dosing exhibits a lower elimination rate [107, 111]. It should be noted that the pharmacological effects of theophylline are also affected by the dosing time. For example, theophylline dosing in the evening controls the nocturnal dip of bronchial patency with no major side effects in patients with nocturnal asthma [332]. Animals are more resistant to theophylline-induced toxicity when the drug is administered in the late light phase than at other times [333]. Although the chronoefficacy of theophylline in treating asthma has been shown to be associated with the circadian rhythms in disease

9 Role of Pharmacokinetics in Chronotherapeutics

parameters such as bronchial patency and dyspnea, chronopharmacokinetics cannot be ruled out [334, 335].

9.5.9

217

contribution

of

Traditional Chinese Medicines (TCMs)

The toxicities of two famous TCMs, named Leigongteng (Tripterygium wilfordii Hook F.) and Fuzi (lateral root of Aconitum carmichaeli), have been shown to depend on the dosing time [195, 336]. Mice are more sensitive to Leigongteng or Fuzi (oral gavage) in the light phase than in the dark phase. This is because CYP3A11 (an ortholog of human CYP3A4), the key enzyme for detoxification of the toxic ingredients of Leigongteng (triptolide) and Fuzi (aconitine, hypaconitine, and mesaconitine), shows significant diurnal rhythm with higher protein level and activity in the dark period in mouse liver [127, 195, 336]. The chronotoxicity of these two TCMs is well correlated with temporal metabolism and pharmacokinetics of the toxic ingredients. CYP3A11 expression is regulated by the clock components CLOCK and BMAL1 through DBP and HNF4α (two transcriptional activators of Cyp3a11) [127]. Ablation of Clock or Bmal1 reduces hepatic CYP3A11 levels and blunts its diurnal rhythm, sensitizing mice to toxicity induced by Leigongteng or Fuzi and abolishing the time dependency of toxicity [195, 336]. Similar circadian events are observed in mice intraperitoneally injected with single ingredient (i.e., triptolide, aconitine, or hypaconitine) [127, 182].

9.5.10 Valproate Valproate is primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches [337]. Valproate is better absorbed when orally dosed in the morning (higher Cmax and shorter Tmax) than in the evening in humans [115, 119, 121]. The rhythm in gastrointestinal function is the key determinant of valproate chronopharmacokinetics, because there are no circadian variations in valproate pharmacokinetics after intravenous or rectal administration [115, 119]. In addition, higher clearance in the dark period may also contribute to valproate chronopharmacokinetics in both humans and mice [116, 118, 244, 245]. In mice, the electroshock seizure threshold and acute toxicity (mortality) induced by valproate change according to time of the day, with stronger effects in the light phase [245]. Strikingly, reverse feeding completely alters the circadian patterns of valproate pharmacokinetics and pharmacodynamics in mice [245]. Likewise, changing meal condition between morning and evening abolishes the circadian rhythms in valproate absorption and pharmacokinetics in humans [121]. Thus, it is proposed that the dosing time may impact the clinical therapeutic response to valproate.

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Chrono-Drug Delivery Systems

Chronotherapeutics has promoted the design of novel drug formulations and development of programmable-in-time drug delivery pumps, aiming at delivering drugs at specific circadian time windows [338–340]. In this part, we present various chronopharmaceutical technologies that can be applied to time-controlled (or timespecific) drug delivery.

9.6.1

CEFORM®

CEFORM® is based on “melt-spinning” method and can produce uniformly sized and shaped microspheres consisting of biodegradable polymer and bioactive pharmaceutical agents. The microspheres obtained by this technology are almost perfect spheres with a diameter of 150–180 μm. These microspheres can be used in a variety of dosage forms, such as capsules, suspensions, tablets, and effervescent tablets. For the purpose of controlled release, the microspheres can be coated with an enteric coating. This technology has been used to develop a one-day diltiazem formulation, Cardizem® LA.

9.6.2

CHRONOTOPIC®

CHRONOTOPIC® consists of a drug-containing core and a release-delaying HPMC layer. The lag-time is controlled by the thickness of coat and the viscosity grade of HPMC. This system is suitable for both single and multiple unit dosage forms such as capsules and tablets.

9.6.3

CODAS®

CODAS® (Chronotherapeutics Oral Drug Absorption System) is a multiparticulate system designed for bedtime dosing that delays drug release for 4–5 h. The delay is provided by the level of nonenteric release controlling polymer (a mixture of both water-soluble and water-insoluble polymers) applied to the drug-loaded beads. Upon contact with the gastrointestinal fluid, the water-soluble polymer gets dissolved slowly (forms pores on the coating layer) and the drug diffuses through the resulting pores. The water-insoluble polymer acts as a barrier in maintaining the controlled release of the drug. The release process is independent of pH, food, and posture. This technology has been applied to make Verelan® PM, an extended-release formulation of verapamil.

9 Role of Pharmacokinetics in Chronotherapeutics

9.6.4

219

CONTINR

CONTINR technology is developed by Purdue Pharma. By melting the cellulose polymer with aliphatic alcohol in volatile polar solvent, molecular coordination complexes are formed between the cellulose polymer and the nonpolar solid aliphatic alcohol. The resulting complex has a uniform porosity (semipermeable matrixes) and is suitable for controlled-release formulations. This technology has been used to develop sustained-release tablets of drugs such as aminophylline, morphine, and theophylline. It offers tight control over the amount of drug released into the bloodstream and reduces the dosing frequency.

9.6.5

DIFFUCAPS®

DIFFUCAPS® is a multiparticulate technology developed by Reliant Pharmaceuticals LLC. It is a versatile approach for chronotherapy, which delivers drugs into the body in a circadian release fashion. It is first used in the chronotherapeutic delivery of a combination of verapamil and propranolol as an extended-release tablet (Innopran®). Pulsincap® system is one of the most used pulsatile systems based on capsules. It was developed by R. P. Scherer International Corporation, Michigan, USA. Diffucaps® comprises one or more populations of drug-containing particles (beads, pellets, granules, etc.). Each bead population displays a rapid release pattern or a continuous release pattern with a lag time of 3–5 h. The active core of the dosage form may consist of an inert particle or an acidic/alkaline buffer crystal (e.g., cellulose ethers), which is coated with hydrophilic API (active pharmaceutical ingredient)-containing film-forming agents (e.g., HPMC and PVP). This technology has been used to formulate the antihypertensive drug propranolol (Innopran XL).

9.6.6

EGALET®

EGALET® technology is developed by Egalet Ltd, Denmark. It is a delayed release form consisting of an impermeable shell with two lag plugs. Drug is sandwiched between the plugs and released after the erosion of the inert plugs. The lag time depends on time taken to erode the inert plugs. The outer shell is formed by slowly biodegradable polymers (e.g., ethyl cellulose) and plasticizers (e.g., cetostearyl alcohol). The plug matrix is a mixture of pharmaceutical excipients, including polymers such as polyethylene oxide.

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GeoClock®

This technology is developed by Skye Pharma and based on the concept of Geomatrix technology. It is a new multilayer technique designed for constant release of drug. The active core or hydrophilic matrix is coated partially on one or both bases. This portion of the coating controls drug release by adjusting the core hydration process and minimizing the surface area. After contact with the dissolving medium, the coating swells and becomes a gel. The gelling layer is not eroded but acts as a membrane to modulate the release process. By using GeoClock® technology, Lodotra™ has been developed by SkyePharma to treat rheumatoid arthritis.

9.6.8

OROS®

OROS® is a system based solely on osmosis. It can reproducibly deliver the drug to the gastrointestinal tract in a time- or site-specific manner. Drug is stored in a reservoir surrounded by a semipermeable membrane, drilled with a delivery orifice, and formulated into the tablet. This tablet consists of a drug layer and a layer of cosmetically active agent. Once contact with the gastrointestinal fluid, the osmotic agent changes its characteristic from a nondispensable viscosity to a dispensable viscosity. As a result, the active pharmaceutical is pushed away through the channel by the pump effect of the osmotic agent. It is generally used to design an extended release tablet (e.g., Covera-HS®).

9.6.9

PORT®

PORT® (programmable oral release technology) is a programmed drug-releasing system consisting of a polymeric core. In the capsule form, the gelatin capsule is coated with a water permeable, rate-controlling polymer. The mixture of drugs and osmotic agents is kept inside the capsule shell. Immediate release compartment can be added if necessary. The content swells to remove the plug, and then the active pharmaceutical is released. The lag time depends on the thickness of the wall, composition and amount of the osmotic contents, and the length of the hydrogel plug.

9.6.10 TIMERx® TIMERx® is a hydrogel-based, controlled release device that can form different release kinetics (from zero order to chronotherapeutic release) by controlling the

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interaction between molecules. This system is made by mixing xanthan and locust bean gums with dextrose. In the presence of water, the physical interaction between these components leads to the formation of a strong binding gel. The penetration rate of water molecules into the TIMERx gum matrix determines the release process of active drug substance in the gastrointestinal tract. The system can accurately control drug release by changing the ratio of gums, tablet coating, and manufacturing process. This technology has been used in the development of oral, controlledrelease opioid analgesic oxymorphine.

9.6.11 Controlled-Release Microchip The solid-state silicon microchip is a microfabrication technology and delivers active pharmaceutical gradients in a pulsatile manner. This system can provide controlled release of single and multiple chemicals as needed. The release mechanism is based on the electrochemical dissolution of a thin anode film that covers a chemical microreservoir in the form of a solid, liquid, or gel. This technique has the potential to design chrono-modulated drug delivery system that can be better controlled in terms of drug release kinetics to meet biological requirement over the time.

9.6.12 Chrono-modulating Infusion Pumps To achieve better therapeutic overcome (particularly in cancer treatment), the onset/ offset times of infusion and variation in flow rate (constant, sinusoidal, or gradually increasing/decreasing) need to be adjusted according to the circadian time. The concept of chrono-drug delivery has triggered the industrial development of nonimplantable multichannel programmable-in-time pumps, including Melodie®, programmable Synchromed®, Panomat® V5 infusion, and Rhythmic® pumps.

9.6.13 Three-Dimensional Printing® Three-dimensional printing is a rapid prototyping technology based on solid freeform fabrication methods. It has been applied to the fabrication of complex oral dosage delivery pharmaceuticals consisting of complicated internal geometries, varying densities, diffusivities, and chemicals. For example, immediate-extended release tablets, dual pulsatory tablets, and pulse release, breakaway tablets.

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9.6.14 Physicochemical Modification of API The physicochemical properties of API may meet the chronopharmaceutical demands through structural modification. The maximum plasma concentration of the drug (Tmax) varies upon introducing new substitution to the original compound. This strategy is effective when drug bioavailability is limited by solubility and permeability. For example, lovastatin and simvastatin are lactone prodrugs that are modified in the liver to form active hydroxy acids (less water soluble). Other physicochemical methods used for chronopharmaceutical delivery include selecting the form of salt, chirality, and controlling particle size.

9.7

Concluding Remarks

Circadian rhythms in physiological processes have significant impact on drug absorption, distribution, metabolism, and excretion. Indeed, pharmacokinetic studies in humans and experimental animals have revealed that dosing time is a key determinant for the disposition and pharmacokinetics of many drugs. The diurnal variations in pharmacokinetics have been shown to, at least partly, contribute to circadian rhythms in drug efficacy and toxicity. However, current chronopharmacological studies were performed under a single drug dose. Multiple doses and steady-state studies are helpful in the future to confirm the chronopharmacokinetics of drugs. In addition to chronopharmacokinetics, the rhythms in drug targets and disease symptoms may also contribute to dosing time-dependent drug effects. A recent research discovered that 43% of all protein-coding genes are rhythmically transcribed somewhere in the body [341]. Intriguingly, these rhythmic genes cover the great majority of direct targets of the best-selling drugs and World Health Organization essential medicines, suggesting that the diurnal variations of drug targets might have significant influences on drug effects [341]. Understanding the rhythms of disease symptoms and drug pharmacokinetics/pharmacodynamics will greatly facilitate the development of optimized dosing schedules, which are necessary for the improvement of treatment responses and patients’ quality of life. Compared with conventional treatment schedule, chronotherapeutic strategy has resulted in up to 5-fold better tolerability and a doubling in efficacy [342]. Although chronotherapy research has demonstrated encouraging results, chronotherapeutic schedules are not commonly used in routine clinical practice, partly due to the lack of a clear mechanistic basis. To date, dosing time is indicated in the drug label instructions for very few marketed medications (Table 9.3). In addition, there are a few ongoing clinical trials worldwide investigating the influences of circadian time on drug responses. Efforts are needed in the future to decipher the mechanistic basis for drug chronopharmacokinetics and chronopharmacodynamics, and to develop more effective therapeutic schedules based on circadian biology.

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Table 9.3 Examples of drugs with FDA-labeled dosing time Drug name Ambien®

Components Zolpidem tartrate

ATRIPLA®

XARELTO®

Efavirenz/ emtricitabine/ tenofovir disoproxil fumarate Insulin detemir (rDNA origin) injection Esomeprazole magnesium Methylphenidate hydrochloride Rivaroxaban

ZOCOR

Simvastatin

LEVEMIR®

NEXIUM Ritalin LA®

Manufacturer Sanofi-Aventis US LLC Bristol-Myers Squibb and Gilead Sciences, LLC

Recommendation Once daily immediately before bedtime One tablet once daily taken orally on an empty stomach, preferably at bedtime

Novo Nordisk Inc.

Once daily administration should be given with the evening meal or at bedtime Once daily taken at least 1 h before meals Supposed to be taken daily in the morning Once daily with the evening meal Once a day in the evening

AstraZeneca Pharmaceuticals LP Novartis Pharmaceuticals Corp. Janssen Pharmaceuticals Inc. Merck Sharp & Dohme Corp.

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Chapter 10

Role of Non-Pharmacokinetic Factors in Chronoefficacy Shuai Wang, Yanke Lin, Lu Gao, Zemin Yang, and Dong Dong

Abstract Dosing time accounts for a large variability in efficacy for many drugs. Therefore, chronotherapy with drugs has been shown to maximize health benefits and minimize adverse effects. Circadian factors contributing to time-varying drug effects can be divided into pharmacokinetic and non-pharmacokinetic factors. Main non-pharmacokinetic factors include drug target and disease severity (flares of symptoms) that vary according to time of the day. There is accumulating evidence supporting a tight association between temporal expression of drug targets and timevarying drug effects. Also, aligning drug treatment with the rhythm of diseases shows improved therapeutic outcomes. In this chapter, we review circadian drug targets and discuss their roles in drug chronoefficacy. We also present examples that correlate circadian variations in disease severity with drug chronoefficacy. Keywords Chronotherapeutics · Rhythm · Chronoefficacy · Drug target

10.1

Introduction

Circadian rhythms are endogenous ~24-h rhythms in physiology and behaviors (e.g., body temperature, cell metabolism, and sleep–wake cycle) resulting from adaptation of organisms to daily changes in the environment [1]. Circadian rhythms are driven by the circadian clock system, which consists of three interlocked auto-regulatory transcriptional–translational feedback loops with key clock proteins such as BMAL1, CLOCK, PERs, CRYs, REV-ERBs, and E4BP4 [2, 3]. These interlocked feedback loops generate circadian rhythms in clock-controlled genes through a

S. Wang · Y. Lin · L. Gao · Z. Yang Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, Guangzhou, China D. Dong (*) School of Medicine, Jinan University, Guangzhou, China © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2020 B. Wu et al. (eds.), Circadian Pharmacokinetics, https://doi.org/10.1007/978-981-15-8807-5_10

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combination of cis-elements (E-box, D-box, and RevRE or RORE) [2, 3]. The clockcontrolled genes encode various circadian proteins that play important roles in the regulation of physiological processes. It is well-accepted that dosing time accounts for intra-individual variability in drug effects (can be up to a tenfold) [4]. Dosing time-dependency has been noted for over 300 medications. Chronotherapy has been shown to generate fivefold better drug tolerability and a doubling in drug efficacy as compared to conventional nontime-stipulated treatment [4]. Circadian factors contributing to time-varying drug effects can be divided into pharmacokinetic and non-pharmacokinetic factors. Main non-pharmacokinetic factors include drug target and disease severity (flares of symptoms) that vary according to time of the day. There is accumulating evidence supporting a tight association between temporal expression of drug targets and timevarying drug effects [5]. Also, aligning drug treatment with the rhythm of diseases shows improved therapeutic outcomes. In this chapter, we review circadian drug targets and discuss their roles in drug chronoefficacy. We also present examples that correlate circadian variations in disease severity with drug chronoefficacy.

10.2

Drugs with Chronoefficacy

Chronotherapeutics has been implicated in the treatment of many diseases such as cancers, inflammatory diseases, metabolic diseases, as well as nervous and mental diseases. In this part, some drugs for treating the above diseases are summarized. Particularly, these drugs show dosing time-varying pharmacological effects (i.e., chronoefficacy) (Table 10.1).

10.2.1 Drugs for Cancers 5-FU 5-FU is a commonly used anti-cancer drug and exerts its function in S phase of cell cycle (DNA synthesis). Toxicity and anti-cancer effects of 5-FU are dependent on the dosing time [43]. Methylcholanthrene A-induced sarcoma mice were treated with 5-FU at 2, 6, 10, 14, 18, or 22 h after light onset [7]. The mice show the longest life span when 5-FU is dosed at ZT14, and the shortest life span when drug is dosed at ZT10 [7]. Besides, 5-FU is the most toxic to bone marrow when 5-FU is administered at ZT10 [7]. Based on these findings, the authors proposed that the best dosing time for 5-FU is ZT14, whereas the worst dosing time is ZT10 [7].

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Table 10.1 Examples of drugs with circadian effects Drug 5-FU Erlotinib Sunitinib Roscovitine Pregabalin Irinotecan

Model Mice/ rats Mice Rabbits Mice Mice Mice

Erastin Propofol L-asparaginase Indomethacin Pethidine Prednisolone

Mice Rabbits Mice Mice Mice Humans

Insulin glargine Diazepam

Humans Humans

Theophylline Verapamil Isosorbide dinitrate Amlodipine Dihydrocodeine and tramadol Fentanyl Sulfasalazine TNP-470

Humans Humans Humans Humans Humans Humans Mice Mice

SU1498 Nutlin-3 IFN-β

Mice Mice Mice

Imatinib Lapatinib N,Ndiethylaminobenzaldehyde Gabapentin Rivaroxaban RS102895 7-OH-DPAT Fluvoxamine Berberine

Circadian drug effects Anti-tumor effects: ZT14 > ZT22

Refs [6, 7]

Anti-tumor effects : ZT1 > ZT13 Mean glycaemia drop: ZT1 > ZT13 Anti-tumor effects: ZT3 > ZT19 Anti-allodynic effects: ZT14 > ZT2 Least toxic time dependent on sex and strain: ZT7, ZT11 or ZT15 Anti-tumor effects: ZT6 > ZT18 Degree of anesthesia: ZT3 > ZT9 Anti-tumor effects: ZT6 > ZT18 Anti-analgesic effects: ZT1 > ZT13 Anti-analgesic effects: ZT14 > ZT2 Morning stiffness relieving effects: ZT19 > ZT0 Glucose lowering activity: morning > evening Effects on hypothermic action of ethanol: light phase (10:00–12:00 h) > dark phase (22:00–24:00 h) Anti-asthmatic effects: ZT1 > ZT13 Anti-cardiovascular effects: ZT15 > ZT1 Anti-anginal effects: ZT19 > ZT1 Anti-hypertensive effects: ZT13 > ZT1 Analgesic effects: evening > morning

[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]

[21] [22] [23] [24] [25] [26] [27] [28]

Mice Mice Mice

Pain relief effects : 17:30 > 5:30 Anti-tumor effects: ZT22 > ZT10 Anti-tumor and anti-angiogenic effects: ZT0 > ZT12 Anti- tumor effects: ZT2 > ZT14 Anti-tumor effects: ZT14 > ZT2 Anti-tumor effects: early light phase > early dark phase Anti-tumor effects: ZT2 > ZT14 Anti-tumor effects: ZT23 > ZT13 Anti-tumor effects: ZT14 > ZT2

Mice Rats Mice Mice Mice Mice

Anti-allodynic effects: ZT22 > ZT10 Anti-coagulant effects: ZT2 > ZT14 Anti-atherosclerosis effects: ZT13 > ZT1 Inhibit locomotor activity: ZT14 > ZT2 Anti-immobility effects: ZT14 > ZT2 Anti-colitis effects: ZT10 > ZT2

[35] [36] [37] [38] [39] [40]

[29] [30] [31] [32] [33] [34]

(continued)

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Table 10.1 (continued) Drug Puerarin

Model Mice

Temocapril

Mice

Circadian drug effects Anti-hyperhomocysteinemia effects: ZT10 > ZT22 Anti-hypertension effects: ZT2 > ZT14

Refs [41] [42]

ZT zeitgeber time

Erlotinib Erlotinib is used to treat non-small cell lung cancer. It acts to inhibit the intracellular phosphorylation of tyrosine kinase-related epidermal growth factor receptor (EGFR), a contributor to tumor progression and metastasis [44]. Mice with HCC827 tumor xenografts were treated by gavage with a single daily dose of erlotinib suspension or vehicle for 21 days. The anti-tumor effect of erlotinib is stronger when drug is treated in the early light phase (at 8:00 AM) than drug treated in the early dark phase (at 20:00 PM). This time-dependent anti-tumor effect is tightly associated with the phosphorylation of EGFR [8].

Roscovitine Roscovitine, a cyclin-dependent kinase inhibitor, is currently used in phase II clinical trials for the treatment of various cancers. Tumor growth inhibition is affected by the dosing time of roscovitine in a Glasgow osteosarcoma xenograft mouse model. Mice are orally treated with the drug for 5 days at ZT3 or ZT19. Tumor growth is reduced by 55% following dosing at ZT3, while only 35% reduction of the tumor is observed at ZT19 [10].

10.2.2 Drugs for Inflammation Diseases Berberine Berberine, extracted from Rhizoma coptidis (Huanglian in Chinese), is a wellknown drug used to treat inflammatory disorders such as colitis. The time-varying anti-inflammatory effect of berberine is observed in DSS-induced chronic colitis mice. Berberine dosed at ZT10 generates a better anti-inflammatory effect as evidenced by lower levels of inflammatory factors (i.e., IL-1β, IL-6, and IL-18) and myeloperoxidase activity as compared to ZT2 dosing. However, the concentrations of berberine do not show any differences in plasma or colon between ZT2 and ZT10 dosing [40].

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Prednisone Prednisone is a glucocorticoid medication used to suppress the immune system and to decrease inflammation. In an early double-blind clinical trial with rheumatoid arthritis patients, prednisolone administered at night shows a superior effect on reduction of morning stiffness as compared to drug dosing in the morning [45].

Indomethacin Indomethacin is a non-steroidal anti-inflammatory agent used to treat inflammatory diseases such as arthritis. Oral administration of indomethacin at 9:00 AM significantly reduces the edema induced by carrageenan. However, no anti-inflammatory effects are observed in the edema model treated with indomethacin at 20:00 PM [46]. This circadian effect is probably due to temporal changes in blood flow to the inflammation site [47].

10.2.3 Drugs for Metabolic Diseases Amlodipine Amlodipine, a calcium channel blocker, is used for treating coronary heart disease and as a first-line drug for curing hypertension. A previous study was performed to investigate the effects of amlodipine dosed at different times of the day in hypertensive or normotensive. The improvements in systolic blood pressure, diastolic blood pressure, and heart rates vary according to the administration time. Systolic blood pressure and heart rate are reduced more significantly after amlodipine dosing at 20:00 PM than at 8:00 AM in hypertensive patients [24]. Therefore, evening dosing is a better choice for pharmacotherapy with amlodipine.

Pregabalin Pregabalin is an analgesic agent used in the management of diabetic neuropathy [11]. A previous study demonstrated that streptozotocin-induced diabetes was alleviated by oral administration of pregabalin at ZT2 or ZT14. However, the antiallodynic effect of pregabalin varies according to the dosing time. Higher analgesic effect is observed in mice treated with pregabalin at ZT14 than at ZT2 [11]. Notably, no significant dosing time difference in analgesic effect is observed in mice intraperitoneally administered with pregabalin.

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Isosorbide Dinitrate Anti-anginal drugs such as isosorbide dinitrate are commonly used to maintain the balance between oxygen demand and supply in the myocardium, and to relieve chest pain and reduce acute ischemic events. Healthy volunteers were orally administered with a single dose of isosorbide dinitrate (20 mg) in the morning (8:00 AM) or in the evening (20:00 PM). The effects of isosorbide dinitrate are more pronounced in the evening than in the morning, as evidenced by a more decrease in systolic blood pressure for drug dosed in the evening [23].

Insulin Glargine Insulin glargine is a long-acting insulin used in the management of type I and type II diabetes (T2D). In a clinical study, ten insulin-treated type 2 diabetes patients were monitored during 24-h euglycemic glucose clamp, after insulin glargine injection (0.4 units/kg) either in the evening (22:00 PM) or the morning (10:00 AM) [19]. Glargine administration in the morning shows a stronger effect in the first 12 h than evening dosing. Besides, plasma glucagon levels and lipolysis are suppressed more significantly after evening dosing than morning glargine administration, while plasma insulin and C-peptide levels do not differ [19].

10.2.4 Drugs for Nervous and Mental Diseases Diazepam Diazepam, a widely used antianxiety agent, shows circadian time-dependent changes in efficacy. Diazepam and ethanol can synergistically affect the central nervous system. Ethanol increases spontaneous locomotor activity and hypothermic action. Diazepam impairs the hypothermic effect caused by ethanol in the light phase (10:00–12:00 AM) in mice but does not have such effect in the dark phase (22:00–24:00 PM) [20]. Moreover, diazepam prolongs ethanol-induced sleep in the light phase, enhances its action on locomotor coordination, and decreases the stimulating effect of ethanol on spontaneous locomotor activity in mice [20].

Propofol Propofol is an anesthetic agent commonly used in ambulatory surgery. Dosing timedependent effects have been demonstrated in rabbits for propofol [14]. Rabbits are administered with a single dose of propofol at 10:00 AM, 16:00 PM, or 22:00 PM via short intravenous infusion. The largest and intermediate degree of anesthesia is

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respectively observed in rabbits after 10:00 AM and 22:00 PM dosing. The lowest efficacy of propofol is observed in rabbits after 16:00 PM dosing.

10.3

Drug Target-Based Chronoefficacy

Temporal variations in the expression of drug targets have been recognized as an essential source of chronoefficacy. For the drugs that target circadian proteins, efficacy may be enhanced by administering drugs at the times corresponding to high expression levels of drug targets.

10.3.1 Clock Proteins as Drug Targets REV-ERBα Circadian clock proteins regulate and maintain circadian rhythms in genes and proteins, many of which are drug targets. In some cases, clock proteins themselves are drug targets such as REV-ERBs and RORs (Table 10.2). REV-ERBα protein displays a circadian rhythm with a peak value at ZT8-10 and a nadir around the late night and early morning hours [40]. REV-ERBα is implicated in the regulation of colitis, and activation of REV-ERBα by a small molecule can alleviate experimental colitis [49]. Berberine is identified to be a REV-ERBα agonist, and its temporal antiinflammatory effects are correlated with the expression levels of the target protein REV-ERBα [40] (Fig. 10.1a). Berberine dosed at ZT10 (when REV-ERBα expression is high) shows a stronger anti-inflammatory effect as compared to that dosing at ZT2 (when REV-ERBα expression is low) (Fig. 10.1a) [40]. REV-ERBα is also shown to be a drug target of puerarin for management of hyperhomocysteinemia (Fig. 10.1b) [41]. REV-ERBα regulates hyperhomocysteinemia through modulation of homocysteine catabolism [50]. Puerarin, as an antagonist for REV-ERBα, shows a better efficacy against hyperhomocysteinemia in the daytime (ZT10) than in the nighttime (ZT22) [41] (Fig. 10.1b). In addition to REV-ERBα, RORs are clock proteins that can be targeted by small molecules. Future studies may test whether ROR ligands show dosing time-dependent drug effects and whether these effects are correlated to circadian rhythms of RORs.

10.3.2 Non-Clock Circadian Proteins as Drug Targets A number of non-clock circadian proteins are drug targets that contribute to dosing time-dependent pharmacological effects (Table 10.2). The rhythms of these proteins are thought to be regulated and maintained by the circadian clock system, although

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Table 10.2 Circadian proteins and targeting drugs with circadian pharmacological effects Circadian target MetAP2 VEGF p53 protein

Drug TNP-470 SU1498 Nutlin-3

Disease Tumor Tumor Tumor

IFN receptors mTOR protein PDGFR EGFR EGFR xCT Aldh3a1

IFN-β Everolimus Imatinib Lapatinib Erlotinib Sulfasalazine N,Ndiethylaminobenzaldehyde Gabapentin Rivaroxaban RS102895 7-OH-DPAT Fluvoxamine Berberine Puerarin Pregabalin Temocapril

α2δ-1 subunit Activated factor X CCL2 DRD3 5-HT REV-ERBα REV-ERBα Octn1 Angiotensinconverting enzyme

A

Tumor Tumor Tumor Tumor Tumor Tumor Tumor

Model Mice Mice Mice, UV. BAL-5.4G cells Mice Mice, MCF-7 Mice Mice Mice Mice Mice

Ref [28] [29] [30]

[31] [48] [32] [33] [8] [27] [34]

Neuropathic pain Thrombosis

Mice Rats

[35] [36]

Atherosclerosis Brain diseases Brain diseases Chronic colitis Hyperhomocysteinemia STZ-induced diabetes Stroke

Mice Mice Mice Mice Mice Mice Rats

[37] [38] [39] [40] [41] [11] [42]

ZT2

ZT10

Colitis severity ZT10

ZT2

REV-ERBα

B

Berberine

(agonist)

Colitis severity

ZT10 ZT10

Homocysteine ZT22

ZT22

REV-ERBα

Puerarin (antagonist)

Homocysteine

Fig. 10.1 Circadian effects of berberine (a) and puerarin (b) depend on REV-ERBα expression. Berberine acts as an agonist, whereas puerarin acts as an antagonist. Both berberine and puerarin show superior efficacy at dosing time of ZT10

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the underlying mechanisms are not completely known. In this part, we discuss some examples of non-clock circadian proteins and targeting drugs with circadian pharmacological effects (more examples are provided in Table 10.2).

Methionine Aminopeptidase 2 (MetAP2) MetAP2 plays an important role in the growth of endothelial cells during tumor angiogenesis. TNP-470 targets MetAP2, and is an angiogenesis inhibitor with antitumor efficacy [51]. The anti-tumor effect of TNP-470 is more potent in mice in the early light phase (e.g., ZT0) than in the early dark phase (e.g., ZT12) [28]. This dosing time-dependent anti-tumor effect is closely associated with the 24-h rhythms in MetAP2 expression and activity in tumor masses [52]. The abundance of MetAP2 protein varies according to time of the day with higher levels from the late dark to the early light phase and lower levels from the late light to the early dark phase. The MetAP2 transcription is enhanced by the CLOCK/BMAL1 heterodimer, and this activation effect is inhibited by PER2 or CRY1 in sarcoma180 tumor masses [52].

Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) VEGFR-2 is a primary responder to vascular endothelial growth factor signal and thereby regulates endothelial migration and proliferation [53]. SU1498, a tyrosine kinase inhibitor of VEGFR-2, is used for the treatment of neovascular retinal diseases. The anti-tumor effect of SU1498 is enhanced when administered in the early light phase (e.g., ZT2) compared with the early dark phase (e.g., ZT14) [29]. This circadian anti-tumor effect is attributable to the temporal variations in the production of vascular endothelial growth factor (VEGF, an endothelial cellspecific mitogen that acts mainly through VEGFR-2). Activation of the VEGF signaling pathway induces various downstream events, such as proliferation of endothelial cells and activation of matrix metalloproteinase. The protein abundance of VEGF in the tumor masses is significantly higher at ZT2 than at ZT14 [29]. PER2 and CRY1 act as major regulators of VEGF transcription [29]. CLOCK and BMAL1 cause increases in the VEGF-Luciferase promoter activities, and the activation effects by CLOCK/BMAL1 are repressed by PER2 and CRY1 [29]. Besides, PER2 and CRY1 inhibit HIF-1α/ARNT-induced VEGF transcription by a direct protein interaction between PER2 and HIF-1α [29].

Calcium Channel a2δ-1 Subunit Calcium channel a2δ-1 subunit of VDCC (voltage-dependent Ca2+ channels) is implicated in the development of neuropathy [54]. Gabapentin is a drug that modulates Ca2+ currents by binding to the α2δ-1 subunit [35]. Accumulating clinical evidence supports the effectiveness of this drug in management of diverse

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neuropathic pain. Gabapentin dosed at 5:00 AM shows more significant antiallodynic effects with alleviated tactile allodynia in a mouse model of neuropathic pain than drug dosed at 17:00 PM [35]. The time-dependent anti-allodynic effects are associated with circadian oscillations in expression of the drug target calcium channel a2δ-1 subunit [35].

5-Hydroxytryptamine (5-HT) Impaired brain 5-HT function is a core pathogenic factor for depressive illness [55]. Fluvoxamine is a specific 5-HT uptake inhibitor used in treatment of depressive illness [56]. The anti-immobility effect of fluvoxamine is more potent in the early dark phase without increasing locomotor activity [39]. The rhythmicity in the extracellular 5-HT level is suggested to be the main mechanism underlying 24-h rhythm of the anti-immobility effect of fluvoxamine [39]. Time-dependent changes in expression and uptake activity of serotonin transporter (SERT, a member of the Na+/Cl- dependent transporter family) in the midbrain probably account for the rhythmicity in extracellular 5-HT level [39]. Brain fluvoxamine concentrations at 0.5 h after drug injection show no significant difference between 9:00 AM and 21:00 PM dosing, suggesting a negligible role of pharmacokinetics in circadian antiimmobility effect of fluvoxamine [39].

Interferon-α (IFN-α) Receptor IFN-α receptor is a virtually ubiquitous membrane receptor that binds IFN-α, a type I IFN cytokine. IFN-α shows anti-viral activity by inducing protective genes that inhibit viral replication and impede viral dissemination. Dosing time-dependent changes in the anti-viral activity of IFN-α are observed (9:00 AM > 21:00 PM) in ICR mice, as evidenced by higher 20 -50 -oligoadenylate synthetase activity in plasma at 24 h after IFN-α injection for dosing at 9:00 AM than at 21:00 PM [57]. It was proposed that the rhythmicity in both IFN-α receptor function and pharmacokinetics are the basis for the temporal changes in the pharmacological effect [57]. The number of IFN-α receptor and the expression of interferon-stimulated genes in lymphocytes are higher at 9:00 AM than at 21:00 PM after treatment with IFN-α. IFN-α is cleared more rapidly at dosing time of 21:00 PM than 9:00 AM dosing.

Platelet-Derived Growth Factor (PDGF) Receptors PDGF receptors are cell-surface tyrosine kinase receptors that are implicated in the pathogenesis of a number of tumor types [58]. Imatinib is a drug that inhibits the function of PDGF receptors [32]. The growth of tumor cells implanted in mice is more severely inhibited by imatinib dosing in the early light phase (e.g., ZT2) than in the early dark phase (e.g., ZT14) [32]. This circadian anti-tumor effect is closely

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related to temporal expression of PDGF receptors [32]. The anti-tumor efficacy of imatinib is much better when drug dosed at ZT2, the time corresponding to the peak expression of PDGF receptors.

Coagulation Factor (FX) FX is associated with an increased risk for venous thromboembolism [59]. Rivaroxaban, an inhibitor of FX, is used in the treatment of venous thromboembolism and the prevention of stroke in patients with non-valvular atrial fibrillation [36]. A low dose of rivaroxaban at ZT2 shows an inhibitory effect on thrombus formation, while dosing at ZT14 has no significant effects [36]. This time-dependent effect on thrombus formation is in accordance with the rhythm of FX expression, with a peak value at ZT4 and a tough value at ZT12 [36]. Notably, the role of pharmacokinetics in circadian effect of rivaroxaban is excluded [36].

10.4

Rhythmic Disease-Based Chronoefficacy

Certain diseases display circadian rhythms in their severity or in flares of symptoms. Such diseases are defined as “rhythmic diseases” here. Examples of rhythmic diseases are rheumatoid arthritis (RA), colitis, asthma, osteoarthritis, cardiovascular diseases, and allergic rhinitis [60]. Dosing time is a significant variable determining pharmacological effects of drugs treating rhythmic diseases, due to temporal variations in diseases severity (flares of symptoms). Aligning drug treatment with the rhythm of diseases therefore can achieve better efficacy and/or minimal adverse effects. RA is a chronic inflammatory disease, which is well known for its diurnal variations in severity as manifested by great joint pain, stiffness, and functional disability in the morning [61–63]. Prednisone is a glucocorticoid medication used for the management of RA. It acts to suppress the immune system and decrease inflammatory responses. A clinical study demonstrated a better efficacy for prednisone administration at night [64]. This study identified a significant improvement in joint stiffness, joint pain, and circulating concentrations of IL-6 when prednisone is administered at 2:00 AM versus 7:30 AM [64]. Consistently, in another clinical trial, prednisolone administered at night is found to reduce or eliminate morning stiffness in RA patients more significantly as compared to drug given in the morning [45]. A modified-release prednisone tablet, which can release the drug with a delay of 4 h after ingestion, has been developed. It showed superior effects when taken at bedtime as compared to morning time [65]. Chronic colitis is another case with a diurnal rhythm in disease severity. A recent study reported that the colitis severity (reflected by the levels of malondialdehyde and myeloperoxidase in the colon) varied according to the circadian time with a nadir at ZT10-14 in mice [40]. Diurnal (and seasonal) rhythmicity in chronic colitis

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may also be observed in humans [66]. Berberine displays anti-inflammatory effects on chronic colitis in a dosing time-dependent manner with a better treatment outcome at ZT10 than at ZT2. The diurnal rhythm of disease severity contributes partly to these time-varying pharmacological effects (another factor is the diurnal rhythm of REV-ERBα as a drug target). Therefore, dosing time for berberine should be optimized by taking both circadian colitis severity and rhythmic drug target into consideration.

10.5

Concluding Remarks

Temporal variations in expression of drug targets (including circadian clock components) and diurnal rhythms in disease severity (flares of symptoms) are main sources of drug chronoefficacy in addition to circadian pharmacokinetics (described in detail in Chap. 9). In general, drug efficacy can be enhanced by administering drugs at the time when the drug target is expressed the most or by aligning drug treatment with the rhythm of disease. Circadian clock directly or indirectly generates and regulates circadian rhythms in non-clock molecular targets that are tightly associated with drug chronoefficacy. Besides chemotherapeutic drugs, target-based chronoefficacy is also applicable to the drugs for treating many other types of diseases such as neuropathic pain, thrombosis, metabolic disorders, and colitis. It is envisioned that the mechanism-based chronoefficacy would facilitate the devolvement of chronotherapy.

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