Human drug metabolism

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  • 1.Human Drug Metabolism An IntroductionMichael D. Coleman Aston University, Birmingham

2. Human Drug Metabolism 3. Human Drug Metabolism An IntroductionMichael D. Coleman Aston University, Birmingham 4. Copyright 2005John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777Email (for orders and customer service enquiries): Visit our Home Page on or 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, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. Requests to the Publisher should be addressed to the Permissions Department, John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England, or emailed to, or faxed to (+44) 1243 770620. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The Publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the Publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Ofces John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 22 Worcester Road, Etobicoke, Ontario, Canada M9W 1L1 Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Library of Congress Cataloging-in-Publication DataBritish Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN-13 978-0-470-86352-8 (HB) ISBN-10 0-470-86352-8 (HB)ISBN-13 978-0-470-86353-6 (PB) ISBN-10 0-470-86353-6 (PB)Typeset in 101/2 /121/2 pt Sabon by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound in Great Britain by Antony Rowe Ltd., Chippenhum, Wilts This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production. 5. For Mark, Carol and Devon 6. ContentsPreface 1Introduction 1.1 1.2 1.3 1.4 1.5 1.62xiTherapeutic window Consequences of drug concentration changes Clearance Hepatic extraction and intrinsic clearance First pass and plasma drug levels Drug and xenobiotic metabolism1 1 4 6 8 9 113Drug Biotransformational Systems Origins and Aims132.1 2.2 2.3 2.4 2.5 2.613 14 14 17 18 19Biotransforming enzymes Threat of lipophilic hydrocarbons Cell communication Potential food toxins Sites of biotransforming enzymes BiotransformationHow Phase I Systems Metabolize Substrates233.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 3.12 3.13 3.14 3.1523 23 24 26 30 30 36 39 40 42 44 48 53 55 56Introduction Capture of lipophilic molecules Cytochrome P450s classication and basic structure CYPs main and associated structures CYP substrate specicity and regulation Main human CYP families Cytochrome P450 catalytic cycle Real-life operations How CYP isoforms operate in vivo Aromatic ring hydroxylation Alkyll oxidations Rearrangement reactions Other oxidation processes Reduction reactions Control of CYP metabolic function 7. viii4CONTENTS5Induction of Phase I Systems574.1 4.2 4.3 4.4 4.557 60 61 62 70Introduction Causes of accelerated clearance Enzyme induction Mechanisms of enzyme induction Induction general clinical aspects6Phase I Enzyme Inhibition755.1 5.2 5.3 5.4 5.5 5.675 78 79 89 91 95Phase II and III Processes 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.117Introduction Glucuronidation Sulphation The GSH system Glutathione S-transferases Epoxide hydrolases Acetylation Methylation Esterases/amidases Amino acid conjugation (glycine or glutamate) Phase III transport processesFactors Affecting Drug Metabolism 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.98Introduction Inhibition of metabolism general aspects Mechanisms of inhibition Cell transport systems and CYP3A inhibitors Clinical consequences of drug inhibition Use of inhibitors for positive clinical intervention101 101 103 113 116 119 123 124 126 126 127 127131Introduction Genetic polymorphisms Effects of age on drug metabolism Effects of diet on drug metabolism Gender effects Smoking Effects of ethanol on drug metabolism Effects of disease on drug metabolism Summary131 132 148 151 154 155 156 161 161Role of Metabolism in Drug Toxicity1638.1 8.2 8.3 8.4 8.5 8.6 8.7Adverse drug reactions: denitions Reversible drug adverse effects: Type A Irreversible toxicity (Type B) Type B1 necrotic reactions Type B2 reactions: immunotoxicity Type B3 reactions: role of metabolism in cancer Summary of biotransformational toxicity163 164 171 176 187 198 214 8. CONTENTSAppendix AMethods in Drug Metabolism A.1 Introduction A.2 Human liver microsomes A.3 Human hepatocytes A.4 Heterologous systems A.5 Toxicological metabolism-based assays A.6 In silico studiesAppendix BMetabolism of Major Illicit Drugs B.1 B.2 B.3 B.4 B.5 B.6 B.7Appendix CExamination Techniques C.1 C.2 C.3 C.4Appendix DIntroduction Opiates Cocaine Hallucinogens Amphetamines: ecstasy (MDMA) Cannabis PCPIntroduction A rst-class answer Preparation The day of reckoningSummary of Major CYP Isoforms and Their Substrates, Inhibitors and Inducersix215 215 216 218 218 219 222225 225 225 230 232 236 240 243247 247 247 248 251253Suggested Further Reading255Index263 9. Preface Throw physic to the dogs; Ill none of it exclaims the eponymous Macbeth in Act 5, Scene 3, in one of Shakespeares shortest and most violent plays. This response to the lack of efcacy and severe toxicity of early seventeenthcentury therapeutics unfortunately has some resonance today. Despite the spectacular advances made in the last 50 years, many medicines in practice are neither benecial nor safe. Indeed, increasing numbers of patients are dying as a result of their treatment, rather than their condition. There are many reasons for our inability to eradicate iatrogenic (literally, physician induced) disease; these might include pharmacological interactions or factors relating to the patients condition. However, the metabolism of drugs by the patients own systems can have a powerful inuence on the success of treatment. This book is intended to provide a basic grounding in human drug metabolism, although it is useful if the reader has some knowledge of biochemistry, physiology and pharmacology from other sources. In addition, a qualitative understanding of chemistry can illuminate many facets of drug metabolism and toxicity. Although chemistry can be intimidating, I have tried to make the chemical aspects of drug metabolism as user-friendly as possible. Regarding the layout of the book, Chapter 1 uses the idea of the therapeutic window to outline how both efcacy and toxicity are dependent on drug concentration, which is in turn linked to the rate of drug removal from the system. Biological systems actively eliminate small xenobiotic (foreign) molecules and how quickly this happens is a strong determinate of treatment outcome. Chapter 2 tries to put the metabolism of drugs in the context of other biological processes. Human metabolizing systems must synthesize endogenous molecules, inactivate them when their purpose is served and defend the body from foreign molecules. Drugs t into the latter category and are treated by biological systems as foreign and unwelcome. Chapter 3 outlines how human metabolizing systems have availed themselves of highly specialized metabolizing enzymes of bacterial and eukaryotic origin, particularly cytochrome P450s. Phase I, the initial, mainly oxidative, phase of metabolism, begins the process of the conversion of lipophilic drugs to easily excreted water-soluble metabolites. The chapter considers the remarkable exibility and capability of these oxidative enzymes. Chapter 4 reveals the mechanisms whereby the presence of some drugs can induce a massive adap- 10. xiiPREFACEtive increase in the metabolizing capability of cytochrome P450s. The threat to clinical drug efcacy posed by the resulting acceleration of drug removal from the body is outlined in a number of drug classes. By contrast, the inhibition of drug-metabolizing systems described in Chapter 5 is shown to cause life-threatening drug accumulation in a very short space of time. The mechanisms of cytochrome P450 inhibition are explained in the context of the main pharmacological features of enzyme inhibition. Chapter 6 illustrates the companion processes for Phase I, which are Phases II and III. In Phase II, large hydrophilic molecules are either attached directly to drugs or Phase I metabolites with the object of increasing their water solubility and molecule weight. This process, in concert with Phase III efux pump systems, facilitates the removal of the metabolites from cells to the urine and the bile. Chapter 7 discusses other factors that inuence drug-metabolizing processes, such as genetic polymorphisms, age, gender, diet, alcohol intake and diseas