Drug Transporters: Molecular Characterization and Role in Drug Disposition

536 Pages·2014·10.931 MB·English

by  Guofeng You, Marilyn E. Morris, Binghe Wang

1.25”
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his book offers a comprehensive guide to drug transporters that influence the absorption, SECOND Wiley Series in Drug Discovery and Development
distribution, and elimination of drugs in the body. Since publication of the first edition, EDITION
Binghe Wang, Series Editor
there have been significant advances in the field: new transporters have been identified,
new regulatory pathways have been discovered, and sophisticated techniques for validating
transport processes have been developed. These have led to a better understanding of the
physiological roles and clinical implications of these transporters.
You Edited by
Retaining the same basic format as its predecessor, the second edition of Drug Transporters: Morris
Guofeng You
Molecular Characterization and Role in Drug Disposition provides an overview of drug
transporters and presents the principles of drug transport and associated techniques. Several Marilyn E. Morris
new chapters are added and others are thoroughly updated or expanded. This new edition
overviews drug transporters; including their function, regulation, and role in drug disposition
and interactions, as well as experimental approaches for studying drug transport. As a result,
this new edition reflects where the field is today and also gives a perspective on the directions
for the foreseeable future.
D
• Describes drug transporter families, mechanisms, and clinical implications along
with experimental methods for studying and characterizing drug transporters
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• Includes new chapters on multidrug and toxin extrusion proteins, placental u
transport, and in silico approaches in drug discovery
Drug
g
• Has a new chapter covering regulatory guidance for the evaluation of drug transport
in drug development with global criteria used for drug transporters in clinical trials
T
• Provides material ranging from fundamental mechanisms to clinical outcomes,
making the book useful for novice and the expert reader
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Transporters
a
GUOFENG YOU is a Distinguished Professor of Pharmaceutics in the Ernest Mario School of
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Pharmacy at Rutgers University, USA. She has published numerous original research articles in
the field of drug transport. She has been serving on several grant review panels of the National
s
Institutes of Health and is on the editorial boards of leading journals. She was the coeditor for
p
the first edition of this book (Wiley, 2007).
o
MARILYN E. MORRIS is Professor in the Department of Pharmaceutical Sciences at the
Molecular Characterization and
University at Buffalo, The State University of New York, USA. Her research focuses on the role
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of drug transporters in the pharmacokinetics and pharmacodynamics of drugs. She is a Fellow of
t Role in Drug Disposition
the American Association of Pharmaceutical Scientists (AAPS) and the American Association
e
for the Advancement of Science (AAAS) and currently serves on the editorial boards of leading
journals. She was also the coeditor for the first edition of this book (Wiley, 2007).
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s
SECOND EDITION
Cover Image: iStoackphoto © alwyncooper
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Drug TransporTers
Wiley series in Drug Discovery and Development
Binghe Wang, Series Editor
A complete list of the titles in this series appears at the end of this volume
Drug TransporTers
Molecular Characterization and role
in Drug Disposition
Second Edition
edited by
guofeng You
Rutgers, the State University of New Jersey
Piscataway, NJ, USA
MarilYn e. Morris
University at Buffalo, State University of New York
Buffalo, NY, USA
Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data:
Drug transporters (2007)
Drug transporters : molecular characterization and role in drug disposition / edited by Guofeng You, Marilyn E. Morris. – Second edition.
p. ; cm.
Includes index.
ISBN 978-1-118-48993-2 (cloth)
I. You, Guofeng, editor. II. Morris, Marilyn Emily, editor. III. Title.
[DNLM: 1. Biological Transport–physiology. 2. Membrane Transport Proteins–physiology. 3. Pharmacokinetics. QU 120]
R857.B52
571.6′4–dc 3
2014008367
Printed in the United States of America
10 9 8 7 6 5 4 3 2 1
This book is dedicated to our students, postdocs, and colleagues
who have challenged and inspired us in our careers, and
to our families William, Sarah, Jacqueline and
Kathleen Morris and Yifan and Peter Zhou who remain
a continuing source of love and support in our lives.

Contents
Preface to the second edition xvii
Preface to the First edition xix
List of Contributors xxi
1 overview of Drug transporter Families 1
Guofeng You and Marilyn E. Morris
1.1 What Are Drug Transporters? 1
1.2 Structure and Model of Drug Transporters 1
1.3 Transport Mechanisms 2
1.4 Polarized Expression of Drug Transporters in Barrier Epithelium 2
1.5 Classifications of Drug Transporters 2
1.5.1 Definition of Efflux and Influx Transporters 2
1.5.2 Definition of Absorptive and Secretory Transporters 2
1.5.3 Relationship between Influx/Efflux and Absorptive/Secretory Transporters 2
1.5.4 ABC Transporters and SLC Transporters 4
1.6 Regulation of Drug Transporters 4
References 4
2 organic Cation and Zwitterion transporters (oCts, oCtns) 7
Hermann Koepsell
2.1 Introduction 7
2.2 hOCT1 (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3) 7
2.2.1 Basic Functional Properties of OCT1–3 8
2.2.2 Structure and Proposed Transport Mechanism of OCT1–3 9
2.2.3 Comparison of Substrate and Inhibitor Selectivities of hOCT1–3 11
2.2.4 Distribution of hOCT1 11
2.2.5 Regulation of hOCT1 11
2.2.6 Physiological and Biomedical Roles of hOCT1 14
2.2.7 Pathological Implications of hOCT1 and Therapeutical Aspects 15
2.2.8 Distribution of hOCT2 15
2.2.9 Regulation of hOCT2 15
2.2.10 Physiological and Biomedical Roles of hOCT2 15
vii
viii COnTEnTS
2.2.11 Pathological Implications of hOCT2 and Therapeutical Aspects 16
2.2.12 Distribution of hOCT3 16
2.2.13 Regulation of hOCT3 16
2.2.14 Physiological and Biomedical Roles of hOCT3 16
2.2.15 Pathological Implications of hOCT3 and Therapeutical Aspects 17
2.3 hOCTn1 (SLC22A4) and hOCTn2 (SLC22A5) 17
2.3.1 Functional Properties of hOCTn1 17
2.3.2 Substrates and Inhibitors of hOCTn1 17
2.3.3 Distribution of hOCTn1 18
2.3.4 Regulation of hOCTn1 18
2.3.5 Physiological and Biomedical Roles of hOCTn1 18
2.3.6 Pathological Implications of hOCTn1 and Therapeutical Aspects 18
2.3.7 Functional Properties of hOCTn2 19
2.3.8 Substrates and Inhibitors of hOCTn2 19
2.3.9 Distribution a of hOCTn2 19
2.3.10 Regulation of hOCTn2 19
2.3.11 Physiological Roles and Biomedical Roles of hOCTn2 19
2.3.12 Pathological Implications of hOCTn2 and Therapeutical Aspects 19
2.4 hOCT6 (SLC22A16) 20
2.5 Conclusions 20
References 21
3 organic Anion transporters 25
Kevin T. Bush, Megha Nagle, David M. Truong, Vibha Bhatnagar, Gregory Kaler, Satish A. Eraly,
Wei Wu and Sanjay K. Nigam
3.1 OAT Family 25
3.1.1 Introduction 25
3.1.2 Discovery 27
3.1.3 nomenclature 27
3.2 Molecular Characterization 27
3.2.1 Genomics 27
3.2.2 Protein Structure 28
3.2.3 Mechanism of Substrate Translocation 28
3.3 Expression and Regulation of OATs 29
3.3.1 Tissue Distribution 29
3.3.2 Ontogeny 29
3.3.3 Transcriptional Regulation 30
3.3.4 Posttranslational Regulation 32
3.4 OAT Substrates 32
3.4.1 Substrates 32
3.4.2 Substrate Specificity 33
3.4.3 Inhibitors 34
3.5 Systems Biology of OATs 35
3.5.1 Physiological Role 35
3.5.2 Pathophysiological Role 35
3.5.3 Clinical Pharmacology 35
3.5.4 Remote Communication, Sensing and Signaling 36
3.6 Conclusions 37
Acknowledgments 37
References 37
4 organic Anion-transporting Polypeptides 43
Rommel G. Tirona and Richard B. Kim
4.1 Introduction to the OATP Superfamily 43
4.1.1 Introduction 43
4.1.2 nomenclature 43