Handbook of Drug Metabolism Third Edition DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs Series Executive Editor James Swarbrick PharmaceuTech, Inc. Pinehurst, North Carolina Recent Titles in Series Handbook of Drug Metabolism, Third Edition, Paul G. Pearson and Larry C. Wienkers The Art and Science of Dermal Formulation Development, Marc Brown and Adrian C.
Williams Pharmaceutical Inhalation Aerosol Technology, Third Edition, Anthony J. Hickey and Sandro R. da Rocha Good Manufacturing Practices for Pharmaceuticals, Seventh Edition, Graham P. Bunn Pharmaceutical Extrusion Technology, Second Edition, Isaac Ghebre-Sellassie, Charles E.
Martin, Feng Zhang, and James Dinunzio Biosimilar Drug Product Development, Laszlo Endrenyi, Paul Declerck, and Shein-Chung Chow High Throughput Screening in Drug Discovery, Amancio Carnero Generic Drug Product Development: International Regulatory Requirements for Bioequivalence, Second Edition, Isadore Kanfer and Leon Shargel Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Fourth Edition, Linda A. Felton Good Design Practices for GMP Pharmaceutical Facilities, Second Edition, Terry Jacobs and Andrew A. Signore Handbook of Bioequivalence Testing, Second Edition, Sarfaraz K. Niazi Generic Drug Product Development: Solid Oral Dosage Forms, Second Edition, edited by Leon Shargel and Isadore Kanfer A complete listing of all volumes in this series can be found at www.com Handbook of Drug Metabolism Third Edition Edited by Paul G.
Wienkers CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2019 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U. Government works Printed on acid-free paper International Standard Book Number-13: 978-1-4822-6203-2 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained.
If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, 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.com (http://www.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 registration 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 Names: Pearson, Paul G. Title: Handbook of drug metabolism. Description: Third edition / [edited by] Paul G. | Boca Raton, Florida : CRC Press, 2019.
| Series: Drugs and the pharmaceutical sciences | Includes bibliographical references and index. Identifiers: LCCN 2018057997| ISBN 9781482262032 (hardback : alk. paper) | ISBN 9780429190315 (ebook) Subjects: LCSH: Drugs--Metabolism--Handbooks, manuals, etc. Classification: LCC RM301.1--dc23 LC record available at https://lccn.gov/2018057997 Visit the Taylor & Francis Web site at http://www.com and the CRC Press Web site at http://www.com This book is dedicated to Professors William F.
Trager and Sidney D. Nelson who trained and inspired a generation of drug metabolism scientists. xv Section I Fundamental Aspects of Drug Metabolism 1. The Evolution of Drug Metabolism Research.
Pharmacokinetics of Drug Metabolites. The Cytochrome P450 Oxidative System. Ortiz de Montellano 4. Aldehyde Oxidases an Emerging Group of Enzymes Involved in Xenobiotic Metabolism: Evolution, Structure, and Function.
83 Enrico Garattini and Mineko Terao 5. Foti and Upendra A. Argikar Section II Factors Which Affect Drug Metabolism 6. Non-CYP Drug Metabolizing Enzymes and Their Reactions .163 Shuguang Ma, Ryan H.
Takahashi, Yong Ma, Sudheer Bobba, Donglu Zhang, and S. The Genetic Basis of Variation in Drug Metabolism and Toxicity. 205 Tore Bjerregaard Stage and Deanna L. Inhibition of Drug Metabolizing Enzymes.
Quantitative Approaches to Human Clearance Projection in Drug Research and Development. Sites of Extra Hepatic Metabolism, Part I: The Airways and Lung. Lamb and Christopher A. Sites of Extra Hepatic Metabolism, Part II: Gut .315 Dan-Dan Tian, Emily J.
Cox, and Mary F. Sites of Extra Hepatic Metabolism, Part III: Kidney. Lash vii viii Contents Section III Technologies to Study Drug Metabolism 13. Mass Spectrometry in Drug Metabolism Research: Principles and Common Practice.
The Role of NMR as a Qualitative and Quantitative Analytical Technique in Biotransformation Studies. Walker, Raman Sharma, and Shuai Wang 15. In Vitro Metabolism: Subcellular Fractions. Drug Interaction Studies in the Drug Development Process: Studies In Vitro.
Scott Obach and Kimberly Lapham 17. Enzyme Induction Studies in Drug Discovery and Development. Dekeyser and Jan L. Transporters in Drug Discovery and Development.
485 Yaofeng Cheng and Yurong Lai 19. Experimental Characterization of Cytochrome P450 Mechanism-Based Inhibition. 523 Dan Rock, Michael Schrag, and Larry C. Wienkers Section IV Applications of Metabolism Studies in Drug Discovery and Development 20.
Clinical Drug Metabolism. Tonn, and Bradley K. Managing Metabolic Activation Issues in Drug Discovery. 577 Sanjeev Kumar, Kaushik Mitra, and Thomas A.
Kinetic Differences between Generated and Preformed Metabolites: A Dilemma in Risk Assessment. 605 Thomayant Prueksaritanont and Jiunn H. Numerical Approaches to Drug Metabolism Kinetics and Pharmacokinetics .621 Ken Korzekwa and Swati Nagar 24. Active Metabolites in Drug Development.
Kandel and Jed N. ADME of Antibody Drug Conjugates. 667 Jiajie Yu, Cinthia Pastuskovas, and Brooke M. Rock Contents ix 26.
Managing Reactive Metabolites in Drug Discovery and Development. Applications of 14C Accelerator Mass Spectrometry in Drug Development. 699 Raju Subramanian and Mark Seymour Index. 725 Preface It is almost a decade since the second edition of the Handbook of Drug Metabolism was published.
Since its inception, the goal of the Handbook was to provide a comprehensive text to serve as a graduate course in Drug Metabolism, a useful reference for academic and industrial drug metabolism scientists, but also as an important reference tool for those pursuing a career in drug discovery and development. The third edition of the Handbook of Drug Metabolism has been markedly updated to capture a decade of advances in our understanding of factors that impact the pharmacokinetics and metabolism of therapeu- tic agents in humans. Moreover, we have sought to include new chapters that reflect significant advances that have occurred in major areas viz., the role transporters in drug disposition, active metabolites in drug development, predicting clinical pharmacokinetics, nonP450 biotransformation reactions, pharma- cogenetics in drug metabolism and toxicity, drug interactions, and antibody drug conjugates. The third edition of the Handbook of Drug Metabolism is organized into four sections.
The first three sections capture scientific and experimental concepts around drug metabolism. Section I reviews fundamental aspects of drug metabolism, including a history of drug metabolism, a review of oxidative and non-oxidative biotransformation mechanisms, a review of liver structure, and function and phar- macokinetics of drugs metabolites. Section II details factors that impact drug metabolism, including pharmacogenetics, drug-drug interactions, and the role of extra-hepatic organs in drug biotransforma- tion. Section III provides in depth insights into analytical technologies and methodologies to study drug metabolism at the molecular, subcellular, and cellular levels, and considerations of factors, viz.
enzyme inhibition and induction that influence drug metabolism and therapeutic response. Section IV has been expanded substantially from the second edition to illustrate the highly integrated role of drug metabolism in drug discovery and drug development. In this regard, Section IV focuses on clinical and preclinical drug metabolism studies, safety considerations for drug metabolites (chemically-reactive and non-reac- tive metabolites) in the selection and development of promising therapeutic candidates and highlights the increased focus of regulatory agencies on safety considerations of drug metabolites. The discipline of drug metabolism is now a highly integrated component of contemporary drug dis- covery and development programs—the results of these efforts have lead to only a small number of clinical development candidates that fail in clinical development for unacceptable pharmacokinetic and drug metabolism properties.
This book is dedicated to two groups of exceptional individuals. First, we thank the distinguished aca- demic and industrial leaders (many of whom have contributed to this book) who have trained a genera- tion, or more, of exceptional drug metabolism scientists. Second, we thank the many graduate students, post-doctoral fellows, and industrial colleagues who have challenged us and enriched our lives over the last two decades. We thank all of you for advancing the field of drug metabolism; your efforts have enabled our discipline to advance promising therapeutic agents with increased probability of success in finding medicines to treat serious illness.
Lastly, it has been a privilege to interact with this collection of expert authors, and we would like to express our sincere gratitude to them for their contributions to the third edition to the Handbook of Drug Metabolism. Wienkers xi Editors Paul G. Pearson is the president and CEO of Pearson Pharma Partners, Westlake Village, California, United States. Pearson received his PhD in Pharmaceutical Sciences from Aston University, Birmingham, UK.
He has had an extensive and successful career in pharmaceutical science, previously serving as vice president of Pharmacokinetics and Drug Metabolism at Amgen, Inc. and executive direc- tor of Preclinical Drug Metabolism at Merck & Co, Inc. He is an active member of several international and national professional organizations. Pearson has contributed to numerous peer-reviewed publica- tions and has been an honored invited lecturer at conferences, society meetings, and symposia on drug development, drug metabolism, and drug discovery.
He is actively engaged in the discovery and develop- ment of new human therapeutics in the fields of oncology and neuroscience to make a dramatic difference to the lives of patients. Wienkers is a principal scientist, Wienkers Consulting, Bainbridge Island Washington, United States. Prior to consulting, Dr. Wienkers served as vice president of Pharmacokinetics and Drug Metabolism at Amgen, Inc.
and senior director of Pharmacokinetics, Dynamics, and Metabolism at Pfizer. He obtained his PhD in Medicinal Chemistry from the University of Washington, Seattle, Washington, United States and in 2014 he was awarded the University of Washington, School of Pharmacy Distinguished Alumni Award in Pharmaceutical Science and Research. Larry is a member of several professional societies, where he has served as Chair of American Society of Pharmacology and Experimental Therapeutics Division of Drug Metabolism and in 2013 he was elected as a fellow in the American Association of Pharmaceutical Scientists. Wienkers has published over 80 peer-reviewed publications and book chapters, has been an invited lecturer at conferences and symposia on large- and small-molecule drug metabolism and drug discovery.
xiii Contributors Upendra A. Peter Guengerich Pharmacokinetic Sciences Department Department of Biochemistry Novartis Institutes for BioMedical Research, Inc. Vanderbilt University School of Medicine Cambridge, Massachusetts Nashville, Tennessee Thomas A. Henne Department of Medicinal Chemistry DMPK, Denali Therapeutics School of Pharmacy South San Francisco, California University of Washington Seattle, Washington Emily J.
Cox Providence Medical Research Center Sudheer Bobba Providence Health & Services Department of Drug Metabolism and Spokane, Washington Pharmacokinetics Genentech Inc. Kalgutkar South San Francisco, California Medicinal Sciences Department Pfizer Worldwide Research and Development Yaofeng Cheng Cambridge, Massachusetts Drug Metabolism Gilead Sciences, Inc. Kandel Foster City, California Department of Pharmacology, Toxicology and Therapeutics Joshua G. Dekeyser The University of Kansas Medical Center Department of Pharmacokinetics and Drug Kansas City, Kansas Metabolism Amgen Inc.
Cyrus Khojasteh One Amgen Center Drive Department of Drug Metabolism and Thousand Oaks, California Pharmacokinetics Genentech Inc. Foti South San Francisco, California Department of Pharmacokinetics and Drug Metabolism Ken Korzekwa Amgen Inc.