Drug Metabolism Chemical and Enzymatic Aspects Textbook Edition

DRUG METABOLISM Chemical and Enzymatic Aspects TEXTBOOK EDITION Jack P. Uetrecht University of Toronto Ontario, Canada William Trager University of Washington Seattle, Washington, USA Uetrecht_978-1420061031_TP.indd 2 5/11/07 2:28:26 PM OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 3:29 Char Count= Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 C 2007 by Informa Healthcare USA, Inc. Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10987654321 International Standard Book Number-10: 1-4200-6103-8 International Standard Book Number-13: 978-1-4200-6103-1 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechan- ical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registra- tion for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Uetrecht, Jack P. Drug metabolism : chemical and enzymatic aspects / edited [i.e. compiled] Jack P. Uetrecht, William Trager. – Textbook ed. p. cm. Includes bibliographical references and index. ISBN-13: 978-1-4200-6103-1 (hb : alk. paper) ISBN-10: 1-4200-6103-8 (hb : alk. paper) 1. Drugs – Metabolism – Textbooks. I. Trager, William, 1937– II. Title. RM301.55.U382 2007 615.7 – dc22 2007016201 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com ii OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 3:31 Char Count= Preface Drugs and other xenobiotics can exert a wide variety of pharmacological and toxic effects. In order to understand these effects it is necessary to understand both the structural parameters that are a direct cause of these effects as well as the factors that control the concentration of the drug in the body, such as absorption, metabolism, and elimination. To fully appreciate drug action requires at least minimal expertise in a variety of disciplines such as chemistry, biochemistry, kinetics and biology. While complicated and demanding in its breadth such knowledge is central to the knowledge base of advanced students of Pharmacy, Pharma- cokinetics, Medicinal Chemistry, Pharmacology and Toxicology. However, texts that focus on covering these disciplines in rationalizing drug action are rare. Furthermore, many of the effects are due to metabolites rather than due to the parent drug/xenobiotic and some metabolites, or intermediates that lead to metabolites, are chemically reactive. Therefore, when considering the effects of an agent, all of the metabolites that the body produces from the agent must also be taken into consideration. To try and address the gap in multidisciplinary knowledge required, as the title sug- gests, the focus of this book is on the chemistry, enzymology and to a lesser extent the kinetics of drug metabolism. As indicated above an understanding of this subject at a minimum requires a basic understanding of the chemistry involved. It is also important that these processes be placed into a biological context. Therefore, Chapter 2 entitled "Background for Nonchemists" and Chapter 3 entitled "Background for Chemists" attempt to explicitly confront these issues and provide the necessary background and context. Since chemically reactive metabolites have major implications for toxicity and since understanding their generation and properties requires the spectrum of disciplines outlined above a chapter is devoted to reactive metabolites. Finally, the only way to master the subject is with practice. Sample problems with answers are provided to facilitate this process. Jack P. Uetrecht William Trager iii OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 3:31 Char Count= OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 3:31 Char Count= Contents Preface .... iii 1. Introduction ............................................................ 1 2. Background for Nonchemists ............................................ 4 3. Background for Chemists . ............................................. 18 4. Oxidation Pathways and the Enzymes That Mediate Them ............... 33 5. Reductive Pathways ..................................................... 109 6. HydrolyticPathways .................................................... 120 7. Conjugation Pathways .................................................. 130 8. Reactive Metabolites .................................................... 145 Practice Problems ...................................................... 167 Answers to Practice Problems ........................................... 169 Index . 175 v OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 3:31 Char Count= OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 2:14 Char Count= 1 Introduction The response of different patients to a drug varies widely and, depending on the drug category, from 20% to 75% of patients do not have a therapeutic response (1). In addition, many patients will have an adverse reaction to a drug. There are many reasons for these interindividual differences in drug response, both pharmacokinetic and pharmacodynamic. In order to begin to understand these differences, it is essential to understand what happens to a drug in the body. Most drugs are given orally and some drugs have variable and incomplete absorption. The major determinant of absorption is the physical properties of the drug. Once in the body, most drugs are converted to multiple metabolites. This process can begin in the intestine or liver before the drug even enters the blood stream. Metabolism is often required in order for the body to eliminate a drug. However, some drugs are prodrugs, i.e., in order to exert a therapeutic effect they require metabolism to convert them to an active agent. Examples include enalapril, which has better oral bioavailability than the active agent, enalaprilate, and is readily activated by hydrolysis, and codeine, which must be metabolized to morphine in order to be an effective analgesic (Fig. 1.1). The enzyme that converts codeine to morphine is polymorphic, and about 7% of the North American population lacks the cytochrome P450 (CYP2D6) needed to perform this conversion; now we understand why codeine does not work in these patients while others have an exaggerated response because of very high levels of CYP2D6 (2). There are several such metabolic enzymes that have common genetic polymorphisms caused by differences in a single nucleotide that influences enzyme expression or protein structure. Classically, this leads to a bi- or even trimodal distribution of enzyme activity in a population. In principle, this could be due to differences in intrinsic activity of the enzyme, but in most cases the genetic variant has very low levels of the enzyme, usually because of rapid protein degradation (3). Such polymorphisms can result in an interindividual difference of more than 100 fold in the blood levels of a drug that is metabolized by a polymorphic enzyme. Examples of polymorphic metabolic enzymes are listed in Table 1.1 (2,4,5). Other metabolic enzymes have more of a Gaussian distribution of enzyme activity in a population, i.e., they do not exhibit a classic bimodal distribution. This is because there are no common variants leading to large differences in enzyme activity and/or because the expression of the 1 OTE/SPH OTE/SPH uetrecht IHUS001-Uetrecht May 10, 2007 2:14 Char Count= 2 Drug Metabolism: Chemical and Enzymatic Aspects O O CO2H O O CO2H H H C N C N C2H5 O N HO N hydrolysis CH3 CH3 enalapril enalaprilate H3C H3C N N CYP2D6 O O H3CO OH HO OH codeine morphine FIGURE 1.1 Metabolic conversion of prodrugs to pharmacologically active agents. enzyme is strongly influenced by environmental factors. A good example of such an enzyme is CYP3A4 whose activity also varies greatly from one individual to another. In a recent study, it was found that the CYP3A4 activity of microsomes from different human livers varied by more than a factor of 100 and this correlated strongly with the level of CYP3A4 protein; however, no single factor was found to be responsible for this large variation (6). Furthermore, some metabolic pathways, such as glucuronidation and amino acid conjugation, are deficient at birth thereby making newborns more sensitive to drugs that are cleared by the enzymes involved. In the case of glucuronidation and newborns, this is partic- ularly

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