Handbook of Drug Metabolism

755 Pages·2019·23.251 MB·English

by  Paul G. Pearson, Larry C. Wienkers

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.crcpress.com
Handbook of Drug Metabolism
Third Edition
Edited by
Paul G. Pearson
Larry C. 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.S. 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.S. 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.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 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. (Paul Gerard), 1960- editor. | Wienkers, Larry C.,
editor.
Title: Handbook of drug metabolism.
Description: Third edition / [edited by] Paul G. Pearson, Larry C. Wienkers.
| 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 RM301.55 .H36 2019 | DDC 615.1--dc23
LC record available at https://lccn.loc.gov/2018057997
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at
http://www.crcpress.com
This book is dedicated to Professors William F. Trager and Sidney D. Nelson
who trained and inspired a generation of drug metabolism scientists.

Contents
Preface ......................................................................................................................................................xi
Editors .....................................................................................................................................................xiii
Contributors .............................................................................................................................................xv
Section I Fundamental Aspects of Drug Metabolism
1. The Evolution of Drug Metabolism Research ...............................................................................3
Patrick J. Murphy
2. Pharmacokinetics of Drug Metabolites ........................................................................................17
Philip C. Smith
3. The Cytochrome P450 Oxidative System .....................................................................................57
Paul R. 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. UDP-Glucuronosyltransferases ..................................................................................................109
Robert S. 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. Cyrus Khojasteh
7. The Genetic Basis of Variation in Drug Metabolism and Toxicity .........................................205
Tore Bjerregaard Stage and Deanna L. Kroetz
8. Inhibition of Drug Metabolizing Enzymes ................................................................................223
F. Peter Guengerich
9. Quantitative Approaches to Human Clearance Projection in Drug Research and
Development ..................................................................................................................................253
Nigel J. Waters
10. Sites of Extra Hepatic Metabolism, Part I: The Airways and Lung .......................................279
John G. Lamb and Christopher A. Reilly
11. Sites of Extra Hepatic Metabolism, Part II: Gut .......................................................................315
Dan-Dan Tian, Emily J. Cox, and Mary F. Paine
12. Sites of Extra Hepatic Metabolism, Part III: Kidney ...............................................................339
Lawrence H. Lash
vii
viii Contents
Section III Technologies to Study Drug Metabolism
13. Mass Spectrometry in Drug Metabolism Research: Principles and Common Practice .......367
Bo Wen
14. The Role of NMR as a Qualitative and Quantitative Analytical Technique in
Biotransformation Studies ..........................................................................................................389
Gregory S. Walker, Raman Sharma, and Shuai Wang
15. In Vitro Metabolism: Subcellular Fractions ...............................................................................411
Michael A. Mohutsy
16. Drug Interaction Studies in the Drug Development Process: Studies In Vitro ......................429
R. Scott Obach and Kimberly Lapham
17. Enzyme Induction Studies in Drug Discovery and Development ............................................467
Joshua G. Dekeyser and Jan L. Wahlstrom
18. 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 ............................................................................................................551
Kirk R. Henne, George R. Tonn, and Bradley K. Wong
21. Managing Metabolic Activation Issues in Drug Discovery ......................................................577
Sanjeev Kumar, Kaushik Mitra, and Thomas A. Baillie
22. Kinetic Differences between Generated and Preformed Metabolites: A Dilemma in
Risk Assessment ...........................................................................................................................605
Thomayant Prueksaritanont and Jiunn H. Lin
23. Numerical Approaches to Drug Metabolism Kinetics and Pharmacokinetics .......................621
Ken Korzekwa and Swati Nagar
24. Active Metabolites in Drug Development ..................................................................................639
Sylvie E. Kandel and Jed N. Lampe
25. 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 ...................................679
Amit S. Kalgutkar
27. Applications of 14C Accelerator Mass Spectrometry in Drug Development ...........................699
Raju Subramanian and Mark Seymour
Index ......................................................................................................................................................725