Title Details

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