Human Drug Metabolism Human Drug Metabolism Third Edition Michael D. Coleman Birmingham, UK This third edition first published 2020 © 2020 John Wiley & Sons, Inc. Edition History John Wiley & Sons, Ltd (1e, 2005); John Wiley & Sons, Ltd (2e, 2010) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law.
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Title: Human drug metabolism / Michael D. Description: Third edition. | Hoboken, NJ : Wiley-Blackwell, 2020. | Includes bibliographical references and index.
Identifiers: LCCN 2019032038 (print) | LCCN 2019032039 (ebook) | ISBN 9781119458562 (paperback) | ISBN 9781119458609 (adobe pdf) | ISBN 9781119458616 (epub) Subjects: LCSH: Drugs–Metabolism. | Xenobiotics–Psychological aspects. Classification: LCC RM301.1–dc23 LC record available at https://lccn.gov/2019032038 LC ebook record available at https://lccn.gov/2019032039 Cover Design: Wiley Cover Images: Dapsone antibacterial drug molecule © MOLEKUUL/science source Author Photo: Courtesy of Michael D. Coleman Set in 10/12pt Times by SPi Global, Pondicherry, India 10 9 8 7 6 5 4 3 2 1 For Mark, Carol, and Devon Contents Prefacexv 1 Introduction 1 1.3 Changes in dosage 3 1.4 Changes in rate of removal 4 1.2 Consequences of drug concentration changes 4 1.2 Clearance and elimination 7 1.3 Biotransformation prior to elimination 7 1.5 Clearance: influencing factors 8 1.4 First pass and drug extraction 9 1.1 First pass: gut contribution 9 1.2 First pass: hepatic contribution 10 1.3 First pass: low‐extraction drugs 12 1.5 First pass and plasma drug levels 13 1.2 Changes in clearance and plasma levels 14 1.6 Drug and xenobiotic metabolism 14 References 15 2 Drug Biotransformational Systems – Origins and Aims 17 2.2 Threat of lipophilic hydrocarbons 18 2.1 Signal molecule evolution 19 2.2 Lipophilic hydrocarbons as signal molecules 20 viii CONTENTS 2.4 False signal molecules: bioprotection 22 2.2 Endocrine disruption: problems and solutions 23 2.3 Endocrine disruption: cosmetic and nutraceutical aspects24 2.4 Endocrine disruption: microRNAs 25 2.5 Sites of biotransforming enzymes 26 2.6 Biotransformation and xenobiotic cell entry 27 2.1 Role of the liver 27 2.2 Drug and xenobiotic uptake: transporter systems 29 2.3 Hepatic and gut uptake (influx) transporter systems 30 2.4 Aims of biotransformation 31 2.5 Task of biotransformation 32 2.6 Phase’s I–III of biotransformation: descriptions and classifications 33 2.7 Biotransformation and drug action 34 References 34 3 How Oxidative Systems Metabolise Substrates 37 3.2 Capture of lipophilic molecules 37 3.3 Cytochrome P450s: nomenclature and methods of study 38 3.2 Methods of analysis 40 3.3 CYP key features and capabilities 42 3.4 CYPs: main and associated structures 44 3.3 CYP flexible regions 45 3.4 Substrate binding in CYPs 46 3.5 Homotropic binding in CYPs 47 3.6 Heterotropic binding in CYPs 49 3.7 CYP complex formation 50 3.8 CYP REDOX partners (i): P450 oxidoreductase (POR) 50 3.9 CYP REDOX partners (ii): Cytochrome b552 3.5 Human CYP families and their regulation 54 3.1 CYP regulation: lifespan 55 3.2 CYP regulation: transcriptional 56 3.3 CYP regulation: post‐translational 58 3.6 Main human CYP families 59 3.7 Cytochrome P450 catalytic cycle 71 3.4 Insertion of oxygen into substrate 75 CONTENTS ix 3.5 Release of product 75 3.3 Mechanism of catalysis 78 3.4 Variation and expression 80 3.5 FMOs in drug development 80 3.9 How CYP isoforms operate in vivo81 3.1 Illustrative use of structures 82 3.2 Primary purposes of CYPs 82 3.3 Role of oxidation 83 3.4 Summary of CYP operations 84 3.10 Aromatic ring hydroxylation 84 3.1 Nature of aromatics 84 3.2 Oxidation of benzene 85 3.1 Saturated alkyl groups 86 3.2 Unsaturated alkyl groups 87 3.3 Pathways of alkyl metabolism 89 3.13 Other oxidation processes 94 3.1 Primary amine oxidations 94 3.2 Oxidation of alcohol and aldehydes 96 3.14 Control of CYP metabolic function 97 References 97 4 Induction of Cytochrome P450 Systems 109 4.1 How living systems self‐regulate: overview 109 4.2 Self‐regulation in drug metabolism 112 4.3 Self‐regulatory responses to drugs: summary 117 4.2 Causes of accelerated clearance 117 4.1 Types of inducers 118 4.2 Common features of inducers and clinical significance 120 4.4 Mechanisms of enzyme induction 121 4.2 CYPs 1A1/1A2 and 1B1 induction 122 4.3 CYP 2B6 2C8/2C9/C19 and 3A4 induction 126 4.6 Reversal of induction 141 x CONTENTS 4.7 Cell transport systems and induction: P‐glycoprotein 143 4.8 Induction processes: summary 148 4.5 Induction: general clinical aspects 149 4.2 Anti‐epileptic agents 150 4.3 OTC (over the counter) and online herbal preparations 155 4.5 Oral contraceptives/steroids 160 4.6 Antiviral/antibiotic drugs 161 4.6 Induction: practical considerations 165 4.
inhibition: which ‘wins’? 165 4.8 Induction: long‐term impact 166 References 167 5 Cytochrome P450 Inhibition 183 5.2 Inhibition of metabolism: general aspects 186 5.3 Mechanisms of reversible inhibition 187 5.4 Mechanisms of irreversible inhibition 196 5.2 Mechanism‐based quasi‐irreversible inhibitors 198 5.3 Mechanism‐based irreversible inhibitors 198 5.5 Clinical consequences of irreversible inhibition 200 5.2 Quasi‐irreversible inhibitors: the SSRIs 201 5.3 Mechanism‐based inhibitors: grapefruit juice 213 5.4 Mechanism‐based inhibitors: other juice products 216 5.5 OTC herbal remedy inhibitors 218 5.6 Cell transport systems and inhibition 220 5.1 Uptake (Influx) transporters: OATPs 220 5.2 Efflux transporters: P‐glycoprotein (P‐gp) 222 5.7 Major clinical consequences of inhibition of drug clearance 226 5.2 Torsades de pointes (TdP) 227 5.8 Use of inhibitors for positive clinical intervention 236 5.2 CYP inhibitors and female hormone‐dependent tumours 237 CONTENTS xi 5.3 CYP inhibitors and male hormone‐dependent tumours 238 5.4 CYP inhibitors and manipulation of prescription drug disposition 239 5.5 Use of inhibitors to increase drug efficacy 241 5.6 Use of inhibitors to reduce toxic metabolite formation 242 5.7 Use of inhibitors to reduce drug costs 245 5.8 Use of inhibition in alcoholism 246 5.9 Summary 246 References 246 6 Conjugation and Transport Processes 263 6.2 UGT mode of operation 266 6.4 UGTs and bilirubin 271 6.5 UGTs and bile acids 272 6.6 Role of glucuronidation in drug clearance 273 6.7 Types of glucuronides formed 274 6.8 Control of UGTs 276 6.9 Induction of UGTs: clinical consequences 278 6.10 UGT inhibition: bilirubin metabolism 280 6.11 UGT inhibition: drug clearance 281 6.12 Microbiome and drug metabolism: passengers or crew? 282 6.2 SULT structure related to catalytic operation 287 6.3 Control of SULT enzymes 289 6.4 SULTs and cancer 289 6.4 The GSH system 290 6.2 GSH system maintenance 292 6.1 Structure and location 293 6.2 Mode of operation 295 6.4 Control of GSTs: overview 300 6.5 Control of GSTs and reactive species 301 6.6 Control of GSTs: the nrf2 system 302 6.1 Nature of epoxides 304 6.3 Epoxide hydrolases: structure, mechanisms of action, and regulation306 6.8 Methylation 309 xii CONTENTS 6.10 Amino acid conjugation (mainly glycine) 314 6.11 Phase III transport processes 315 6.2 ABC Efflux transporters 315 6.12 Biotransformation: integration of processes 320 References 322 7 Factors Affecting Drug Metabolism 331 7.3 Genetic polymorphisms in CYP systems 341 7.4 Genetic polymorphisms in nonconjugative systems 369 7.5 Conjugative polymorphisms: acetylation 374 7.6 Conjugative polymorphisms: methylation 381 7.7 Conjugative polymorphisms: UGT 1A1 385 7.8 Conjugative polymorphisms: sulphonation 388 7.9 Other conjugative polymorphisms: Glutathione S‐transferases 389 7.11 Polymorphism detection: clinical and practical issues 392 7.3 Effects of age on drug metabolism 395 7.2 Drug clearance in neonates and children 398 7.4 Effects of diet on drug metabolism 401 7.4 Other vegetable effects on metabolism 404 7.6 Diet: general effects 405 7.7 Effects of ethanol on drug metabolism 412 7.1 Context of ethanol usage 412 7.3 Ethanol and inhibitors of ALDH 414 7.4 Mild ethanol usage and drug clearance 414 7.5 Heavy ethanol usage and paracetamol 415 7.6 Alcoholic liver disease 416 7.7 Effects of cirrhosis on drug clearance 420 7.9 Effects of disease on drug metabolism 424 7.10 Summary 425 References 426 CONTENTS xiii 8 Role of Metabolism in Drug Toxicity 447 8.1 Adverse drug reactions: definitions 447 8.2 Predictable drug adverse effects: type A 448 8.1 Intensification of pharmacologic effect: type A1 448 8.2 Off‐target reversible effects and methaemoglobin formation: type A2 449 8.3 Predictable overdose toxicity: type A3 455 8.3 Unpredictable drug adverse effects: type B 470 8.1 Idiosyncratic and overdose toxicity: similarities and differences 470 8.2 Type B1 necrosis: troglitazone 471 8.3 Type B1 necrosis: trovafloxacin 473 8.4 Type B2 reactions: immunotoxicity 476 8.4 Nature of drug‐mediated immune responses 489 8.2 DRESS/Anticonvulsant hypersensitivity syndrome (AHS) 491 8.3 Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)492 8.5 Prediction of idiosyncratic reactions 499 8.5 Type B3 reactions: role of metabolism in cancer 500 8.1 Sources of risks of malignancy 500 8.2 Risks of malignancy and drug development 501 8.3 Environmental carcinogenicity risks 502 8.5 Dietary carcinogens: acrylamide 513 8.6 Dietary carcinogens: aflatoxins 516 8.6 Summary of biotransformational toxicity 520 References 521 Appendix A Drug Metabolism in Drug Discovery 531 A.1 The pharmaceutical industry 531 A.2 Drug design and biotransformation: strategies 533 A.3 Animal and human experimental models: strategies 537 A.4 In vitro metabolism platforms and methods 539 A.2 Human liver microsomes 541 A.3 Heterologous recombinant systems 542 A.5 Animal model developments in drug metabolism 550 A.2 Genetic modification of animal models 551 A.2 Cell viability assays 554 A.3 ‘One compartment’ cell models 555 A.4 ‘Two compartment’ models 555 xiv CONTENTS A.5 DNA and chromosomal toxicity assays 556 A.6 The Ames test 556 A.9 Toxicology in drug discovery 558 A.7 In silico approaches 561 A.8 Summary 564 References 565 Appendix B Metabolism of Major Illicit Drugs 571 B.8 Charlie Don’t Surf! 616 References 617 Appendix C Examination Techniques 627 C.2 A first‐class answer 627 C.4 The day of reckoning 632 C.5 Foreign students 633 Appendix D Summary of Major CYP Isoforms and Their Substrates, Inhibitors, and Inducers 635 Index 639 Preface In the spring of 1986 in a crackly transatlantic telephone conversation, I recall discussing my impending postdoctoral work at the Walter Reed Army Institute of Research in Washington D., with Dr Melvin H. Heiffer, then Chief of the Pharmacology Section. I distinctly remember him saying that I could look for- ward to ‘a beautiful adventure in Pharmacology’.