Drug Transporters Molecular Characterization and Role in Drug Disposition
, by You, Guofeng; Morris, Marilyn E.; Wang, Binghe
- ISBN: 9781118489932 | 1118489934
- Cover: Hardcover
- Copyright: 9/2/2014
This new edition overviews drug transporters and presents the principles of drug transport and associated techniques, featuring new chapters on multidrug and toxin extrusion proteins, placental transport, in silico approaches in drug discovery, and regulatory guidance for drug transport studies in drug development.
• Describes drug transporter families, mechanisms, and clinical implications along with experimental methods for studying and characterizing drug transporters
• Includes new chapters on multidrug and toxin extrusion proteins, placental transport and in silico approaches in drug discovery
• 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
• Arranges material to go from fundamental mechanisms to clinical outcomes, making the book useful for novice and expert readers
Guofeng You is a Distinguished Professor of Pharmaceutics in the Ernest Mario School of 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 Institutes of Health and is on the editorial boards of leading journals. She was the coeditor for the first edition of this book (Wiley, 2007).
Marilyn E. Morris is Professor in the Department of Pharmaceutical Sciences at the University at Buffalo, State University of New York. She is a Fellow of the American Association of Pharmaceutical Scientists (AAPS) and the American Association for the Advancement of Science (AAAS). and currently serves on the editorial boards of leading journals and was also co-editor for the first edition of this book (Wiley, 2007).
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
1.6 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
2.3 hOCTN1 (SLC22A4) and hOCTN2 (SLC22A5) 17
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
3.2 Molecular Characterization 27
3.3 Expression and Regulation of OATs 29
3.4 OAT Substrates 32
3.5 Systems Biology of OATs 35
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
4.2 Molecular Characteristics of OATPs 44
4.3 Expression and Regulation of OATPs 45
4.4 OATP Substrates and Inhibitors 48
4.5 Pharmacology of OATPs 53
4.6 Physiological/Pathophysiological Roles 57
4.7 Conclusions 58
Acknowledgments 58
References 59
5 Peptide Transporters 67
Stephen M. Carl, Dea Herrera-Ruiz, Rajinder K. Bhardwaj, Olafur Gudmundsson and Gregory T. Knipp
5.1 Introduction 67
5.2 Molecular and Structural Characteristics 69
5.3 Functional Properties 73
5.4 Regulation 74
5.5 Pharmaceutical Drug Screening 80
5.6 Concluding Remarks 83
Acknowledgments 84
References 84
6 Monocarboxylic Acid Transporters 91
Zejian Liu and Lester R. Drewes
6.1 Introduction 91
6.2 Mitochondrial Pyruvate Transporter Family 91
6.3 SLC5 Transporter Family 92
6.4 SLC16 Transporter Family 93
References 99
7 The Nucleoside Transporters CNTs and ENTs 107
Horace T. B. Ho and Joanne Wang
7.1 Introduction 107
7.2 Molecular and Functional Characteristics of CNTs (SLC28) 107
7.3 Molecular and Functional Characteristics of ENTs (SLC29) 112
7.4 Regulation of CNT and ENT Nucleoside Transporters 116
7.5 Physiological and Pathophysiological Functions of CNTs AND ENTs 117
7.6 Therapeutic Significance of CNTs and ENTs 119
7.7 Conclusions and Future Directions 120
Acknowledgment 121
Abbreviations 121
References 121
8 Bile Salt Transporters 127
Jyrki J. Eloranta, Bruno Stieger and Gerd A. Kullak-Ublick
8.1 Overview of the Enterohepatic Circulation of Bile Salts 127
8.2 The Chief Transporters in the Enterohepatic Circulation of Bile Salts 127
8.3 Enterohepatic Bile Salt Transporters in Liver Disease 129
8.4 Control of Bile Salt Transport and Metabolism 130
8.5 N uclear Receptors as Transcriptional Regulators of Bile Salt Homeostasis 130
8.6 FXR-Dependent Mechanisms That Regulate Human Bile Salt Transporter Genes 132
8.7 Cross Talk between the Transcriptional Control of Bile Salt and Drug Transporters 135
8.8 Concluding Remarks and Future Perspectives 135
References 135
9 Multidrug Resistance Protein: P-Glycoprotein 141
Adam T. Clay and Frances J. Sharom
9.1 The P-Glycoprotein Gene Family 141
9.2 Tissue Distribution of P-Glycoprotein 141
9.3 Role of P-Glycoprotein in Human Physiology 141
9.4 P-Glycoprotein Substrates and Modulators 143
9.5 P-Glycoprotein Structure 143
9.6 Subcellular Systems for Studying P-Glycoprotein 146
9.7 ATP Binding and Hydrolysis by P-Glycoprotein 147
9.8 Drug Binding by P-Glycoprotein 148
9.9 P-Glycoprotein-Mediated Drug Transport 148
9.10 Substrate Specificity of P-Glycoprotein and the Nature of the Drug-Binding Site 149
9.11 P-Glycoprotein as a Hydrophobic Vacuum Cleaner or Drug Flippase 150
9.12 Role of the Lipid Bilayer in P-Glycoprotein Function 151
9.13 Mechanism of Action of P-Glycoprotein 153
9.14 Role of P-Glycoprotein in Drug Therapy 154
9.15 Modulation of P-Glycoprotein in Cancer Treatment 154
9.16 Regulation of P-Glycoprotein Expression 155
9.17 P-Glycoprotein Gene Polymorphisms and Their Implications in Drug Therapy and Disease 155
9.18 Summary and Conclusions 156
References 157
10 Multidrug Resistance Proteins of the ABCC Subfamily 161
Anne T. Nies and Thomas Lang
10.1 Introduction 161
10.2 Molecular Characteristics 162
10.3 Functional Properties, Substrate Specificity, and Multidrug Resistance Profiles of Human ABCC/MRPs 163
10.4 Localization of ABCC/MRP Efflux Transporters in Normal Human Tissues and in Human Cancers 167
10.5 Genotype–Phenotype Correlations and Clinical Consequences of Genetic Variants in ABCC Genes 171
10.6 Conclusions and Future Prospects 178
Acknowledgments 179
References 179
11 Breast Cancer Resistance Protein (BCRP) or ABCG2 187
Agnes Basseville, Robert W. Robey, Julian C. Bahr and Susan E. Bates
11.1 Discovery and Nomenclature 187
11.2 ABCG2 Gene and Expression 187
11.3 Physical Properties 191
11.4 Substrates/Inhibitors of ABCG2 194
11.5 Recent Findings in Physiological Function 195
11.6 Predicted Physiological Function from Tissue Distribution 199
11.7 ABCG2 Expression in Cancer and Its Role in Drug Resistance 202
11.8 Genetic Polymorphisms 205
11.9 Conclusion 208
References 208
12 Multidrug and Toxin Extrusion Proteins 223
Stephen H. Wright
12.1 Introduction 223
12.2 Tissue and Subcellular Distribution of MATEs 225
12.3 Functional Characteristics of MATE Transporters 226
12.4 Kinetics and Selectivity of MATE-Mediated Transport 227
12.5 Molecular/Structural Characteristics of MATE Transporters 233
12.6 Regulation of MATE and Activity 236
12.7 Influence of MATEs on Renal OC Clearance and Clinical Drug–Drug Interactions 237
12.8 Conclusions 238
Acknowledgments 238
References 238
13 Drug Transport in the Liver 245
Brian C. Ferslew, Kathleen Köck and Kim L. R. Brouwer
13.1 Hepatic Physiology: Liver Structure and Function 245
13.2 Hepatic Uptake Transport Proteins 245
13.3 Hepatic Efflux Transport Proteins 247
13.4 Regulation of Hepatic Drug Transport Proteins 249
13.5 Disease State Alterations in Hepatic Transport Proteins 253
13.6 Model Systems for Studying Hepatobiliary Drug Transport 255
13.7 Drug Interactions in Hepatobiliary Transport 260
13.8 Interplay between Drug Metabolism and Transport 262
13.9 Hepatic Transport Proteins as Determinants of Drug Toxicity 263
13.10 The Future of Hepatic Drug Transport 263
Acknowledgments 264
References 264
14 Drug Transport in the Brain 273
Tamima Ashraf, Patrick T. Ronaldson and Reina Bendayan
14.1 Introduction 273
14.2 Physiology of the Brain Barriers and Brain Parenchyma 273
14.3 Functional Expression of Drug Transporters in the Brain 274
14.4 Relevance of Drug Transporters in CNS Disorders 283
14.5 Regulation of Drug Transporters by Nuclear Receptors in the Brain 289
14.6 Conclusion 290
References 291
15 Drug Transport in the Kidney 303
Hiroyuki Kusuhara, Takashi Sekine, Naohiko Anzai and Hitoshi Endou
15.1 Introduction 303
15.2 Families of Renal Drug Transporters 305
15.3 Regulation of Renal Drug Transporters 310
15.4 Pharmacokinetic and Pharmacological/Toxicological Aspects 312
15.5 In Vitro Model Systems for Studying Renal Drug Transport 315
15.6 FDA and EMA Draft Guidance/Guideline for Drug–Drug Interaction Studies 316
15.7 Perspectives 316
References 316
16 Drug Transporters in the Intestine 327
Patrick J. Sinko
16.1 Introduction 327
16.2 Intestinal Drug Permeation 327
16.3 Drug Transporters in the Small Intestine 329
16.4 Impact of Small Intestinal Transporters on Oral Absorption of Drugs 331
16.5 Functional Modulation of Intestinal Transporters to Optimize Oral Absorption of Drugs 335
16.6 Concluding Remarks 335
References 335
17 Drug Transport in the Placenta 341
Qingcheng Mao, Vadivel Ganapathy and Jashvant D. Unadkat
17.1 Introduction 341
17.2 Blood–Placental Barrier Relevant to Drug Permeability and Transport 341
17.3 Drug Transporters in Human Placenta 342
17.4 Methods to Study Placental Drug Transport 348
17.5 Summary 349
References 350
18 Experimental Approaches to the Study of Drug Transporters 355
Yoshiyuki Kubo, Akira Tsuji and Yukio Kato
18.1 Introduction 355
18.2 In Vivo Experiments 355
18.3 Isolated Tissue Methods 358
18.4 Primary Cell Cultures and Established Model Cell Lines 359
18.5 Membrane Vesicles 362
18.6 Analysis of Drug Interaction Mechanisms 363
18.7 Perspectives 364
References 365
19 Transporters in Drug Discovery: In Silico Approaches 371
Ayman El-Kattan, Manthena V. Varma and Yurong Lai
19.1 Introduction 371
19.2 Physicochemical Determinants of Hepatobiliary Elimination 371
19.3 In Silico Models for Biliary Excretion 373
19.4 Physicochemical Determinants of Renal Elimination 375
19.5 In Silico Models of Renal Excretion 375
19.6 PhysiCochemical Determinants of Brain Penetration 376
19.7 In Silico Approaches and SAR of Clinical Relevant Transporters 377
19.8 Strategies to Assess Transporter Involvement during Drug Discovery 381
19.9 Conclusions 382
References 382
20 Polymorphisms of Drug Transporters and Clinical Relevance 389
Aparna Chhibber, Janine Micheli and Deanna L. Kroetz
20.1 Genetic Variation and Drug Response 389
20.2 Genetic Variation in Membrane Transporters 390
20.3 Functional Analysis of Transporter Variants 391
20.4 Clinical Significance of Transporter Variants 394
References 398
21 Diet/Nutrient Interactions with Drug Transporters 409
Xiaodong Wang and Marilyn E. Morris
21.1 Introduction 409
21.2 Diet/Nutrient Interactions with Drug Transporters 409
21.3 Conclusions 425
Acknowledgments 427
References 427
22 Clinical Relevance: Drug–Drug Interactions, Pharmacokinetics, Pharmacodynamics, and Toxicity 433
Serena Marchetti and Jan H. M. Schellens
22.1 Introduction 433
22.2 Interactions Mediated by ABC Drug Transporters 433
22.3 Interactions Mediated by Organic Anion and Cation Transporters (Solute Carrier Family, SLC22) 444
22.4 Interactions Mediated by Peptide Transporters (PEPTs, SLC15) 453
22.5 Interactions Mediated by Multidrug and Toxin Extrusion Transporters (MATEs, SLC47) 455
22.6 Interactions Mediated by Monocarboxylate Transporters (MCTs, SLC16) 457
22.7 Interactions Mediated by Nucleoside (Concentrative and Equilibrative) Transporters (CNTs/ENTs, SLC28/29) 458
22.8 Conclusions 460
References 461
23 Regulatory Science Perspectives on Transporter Studies in Drug Development 473
Sue-Chih Lee, Lei Zhang and Shiew-Mei Huang
23.1 Introduction 473
23.2 Regulatory Science Perspectives on Transporter Studies 474
23.3 Recent FDA NDA Review Examples 483
23.4 Conclusion and Future Directions 486
Acknowledgments 486
Abbreviation List 486
References 487
Index 491
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