Main description:

This book offers a comprehensive guide to drug transporters thatinfluence the absorption, distribution, and elimination of drugs inthe body. Since publication of the first edition, there have beensignificant advances in the field: new transporters have beenidentified, new regulatory pathways have been discovered, andsophisticated techniques for validating transport processes havebeen developed. These have led to a better understanding of thephysiological roles and clinical implications of thesetransporters.

Retaining the same basic format as its predecessor, the secondedition of Drug Transporters:
Molecular Characterization and Role in Drug Dispositionprovides an overview of drug transporters and presents theprinciples of drug transport and associated techniques. Several newchapters are added and others are thoroughly updated or expanded.This new edition overviews drug transporters; including theirfunction, regulation, and role in drug disposition andinteractions, as well as experimental approaches for studying drugtransport. As a result, this new edition reflects where the fieldis today and also gives a perspective on the directions for theforeseeable future.

Describes drug transporter families, mechanisms, andclinical implications along with experimental methods for studyingand characterizing drug transporters
Includes new chapters on multidrug and toxin extrusionproteins, placental transport, and in silico approaches in drugdiscovery
Has a new chapter covering regulatory guidance for theevaluation of drug transport in drug development with globalcriteria used for drug transporters in clinical trials
Provides material ranging from fundamental mechanisms toclinical outcomes, making the book useful for novice and the expertreader

Back cover:

This book offers a comprehensive guide to drug transporters thatinfluence the absorption, distribution, and elimination of drugs inthe body. Since publication of the first edition, there have beensignificant advances in the field: new transporters have beenidentified, new regulatory pathways have been discovered, andsophisticated techniques for validating transport processes havebeen developed. These have led to a better understanding of thephysiological roles and clinical implications of thesetransporters.

Retaining the same basic format as its predecessor, the secondedition of Drug Transporters:
Molecular Characterization and Role in Drug Dispositionprovides an overview of drug transporters and presents theprinciples of drug transport and associated techniques. Several newchapters are added and others are thoroughly updated or expanded.This new edition overviews drug transporters; including theirfunction, regulation, and role in drug disposition andinteractions, as well as experimental approaches for studying drugtransport. As a result, this new edition reflects where the fieldis today and also gives a perspective on the directions for theforeseeable future.

Describes drug transporter families, mechanisms, andclinical implications along with experimental methods for studyingand characterizing drug transporters
Includes new chapters on multidrug and toxin extrusionproteins, placental transport, and in silico approaches in drugdiscovery
Has a new chapter covering regulatory guidance for theevaluation of drug transport in drug development with globalcriteria used for drug transporters in clinical trials
Provides material ranging from fundamental mechanisms toclinical outcomes, making the book useful for novice and the expertreader

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 BarrierEpithelium 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, OlafurGudmundsson 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 ANDENTs 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 Salts127

8.2 The Chief Transporters in the Enterohepatic Circulation ofBile Salts 127

8.3 Enterohepatic Bile Salt Transporters in Liver Disease129

8.4 Control of Bile Salt Transport and Metabolism 130

8.5 N uclear Receptors as Transcriptional Regulators of BileSalt Homeostasis 130

8.6 FXR–Dependent Mechanisms That Regulate Human Bile SaltTransporter Genes 132

8.7 Cross Talk between the Transcriptional Control of Bile Saltand 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 ofthe Drug–Binding Site 149

9.11 P–Glycoprotein as a Hydrophobic Vacuum Cleaner or DrugFlippase 150

9.12 Role of the Lipid Bilayer in P–Glycoprotein Function151

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 inDrug Therapy and Disease 155

9.18 Summary and Conclusions 156

References 157

10 Multidrug Resistance Proteins of the ABCC Subfamily161
Anne T. Nies and Thomas Lang

10.1 Introduction 161

10.2 Molecular Characteristics 162

10.3 Functional Properties, Substrate Specificity, and MultidrugResistance Profiles of Human ABCC/MRPs 163

10.4 Localization of ABCC/MRP Efflux Transporters in NormalHuman Tissues and in Human Cancers 167

10.5 Genotype Phenotype Correlations and ClinicalConsequences 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 ABCG2187
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 Distribution199

11.7 ABCG2 Expression in Cancer and Its Role in Drug Resistance202

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 Transporters233

12.6 Regulation of MATE and Activity 236

12.7 Influence of MATEs on Renal OC Clearance and ClinicalDrug 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 Proteins253

13.6 Model Systems for Studying Hepatobiliary Drug Transport255

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 Toxicity263

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 Parenchyma273

14.3 Functional Expression of Drug Transporters in the Brain274

14.4 Relevance of Drug Transporters in CNS Disorders 283

14.5 Regulation of Drug Transporters by Nuclear Receptors in theBrain 289

14.6 Conclusion 290

References 291

15 Drug Transport in the Kidney 303
Hiroyuki Kusuhara, Takashi Sekine, Naohiko Anzai and HitoshiEndou

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 Aspects312

15.5 In Vitro Model Systems for Studying Renal Drug Transport315

15.6 FDA and EMA Draft Guidance/Guideline for Drug DrugInteraction 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 Absorptionof Drugs 331

16.5 Functional Modulation of Intestinal Transporters toOptimize 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 Permeabilityand 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 Transporters355
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 Lines359

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 Approaches371
Ayman El–Kattan, Manthena V. Varma and Yurong Lai

19.1 Introduction 371

19.2 Physicochemical Determinants of Hepatobiliary Elimination371

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 RelevantTransporters 377

19.8 Strategies to Assess Transporter Involvement during DrugDiscovery 381

19.9 Conclusions 382

References 382

20 Polymorphisms of Drug Transporters and Clinical Relevance389
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 Transporters409
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 CationTransporters (Solute Carrier Family, SLC22) 444

22.4 Interactions Mediated by Peptide Transporters (PEPTs,SLC15) 453

22.5 Interactions Mediated by Multidrug and Toxin ExtrusionTransporters (MATEs, SLC47) 455

22.6 Interactions Mediated by Monocarboxylate Transporters(MCTs, SLC16) 457

22.7 Interactions Mediated by Nucleoside (Concentrative andEquilibrative) Transporters (CNTs/ENTs, SLC28/29) 458

22.8 Conclusions 460

References 461

23 Regulatory Science Perspectives on Transporter Studies inDrug Development 473
Sue–Chih Lee, Lei Zhang and Shiew–Mei Huang

23.1 Introduction 473

23.2 Regulatory Science Perspectives on Transporter Studies474

23.3 Recent FDA NDA Review Examples 483

23.4 Conclusion and Future Directions 486

Acknowledgments 486

Abbreviation List 486

References 487

Index 491