Drug Transporters

1 Cover

2 Series Page 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

3 Title Page DRUG TRANSPORTERS Molecular Characterization and Role in Drug Disposition Third Edition EDITED BY GUOFENG YOU Department of Pharmaceutics, Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey Piscataway, NJ, USA MARILYN E. MORRIS Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences University at Buffalo, State University of New York Buffalo, NY, USA

4 Copyright Page

5 Dedication Page

6 LIST OF CONTRIBUTORS

7 PREFACE

8 1 OVERVIEW OF DRUG TRANSPORTER FAMILIES 1.1 INTRODUCTION 1.2 WHAT ARE DRUG TRANSPORTERS? 1.3 STRUCTURE AND MODEL OF DRUG TRANSPORTERS 1.4 TRANSPORT MECHANISMS 1.5 POLARIZED EXPRESSION OF DRUG TRANSPORTERS IN BARRIER EPITHELIUM 1.6 CLASSIFICATIONS OF DRUG TRANSPORTERS 1.7 NOMENCLATURE OF DRUG TRANSPORTERS 1.8 REGULATION OF DRUG TRANSPORTERS 1.9 CONCLUSION REFERENCES

9 2 ORGANIC CATION AND ZWITTERION TRANSPORTERS 2.1 OVERALL INTRODUCTORY SECTION CATION TRANSPORTERS: OCT1, OCT2, OCT3 (OTHER SECTION: SLC19A2, SLC19A3, PMAT)2.2 INTRODUCTION TO THE OCT FAMILY 2.3 OCT1 2.4 OCT2 2.5 OCT3 2.6 OTHER IMPORTANT CATION TRANSPORTERS: SLC19A2, SLC19A3 (THIAMINE TRANSPORTERS), SLC29A4 (MONOAMINE TRANSPORTER) ZWITTERION TRANSPORTERS: OCTN1, OCTN2, SLC22A15 AND SLC22A16 (OTHER SECTION: OCTN3)2.7 INTRODUCTION TO THE ZWITTERION TRANSPORTERS 2.8 OCTN1 2.9 OCTN2 2.10 SLC22A15 2.11 SLC22A16 (FLIPT2, CT2, OCT6) 2.12 OCTN3 2.13 CONCLUSION REFERENCES

10 3 MULTIDRUG AND TOXIN EXTRUSION PROTEINS 3.1 INTRODUCTION 3.2 TISSUE AND SUBCELLULAR DISTRIBUTION 3.3 TRANSPORT ACTIVITY 3.4 STRUCTURE 3.5 EXPRESSION AND REGULATION 3.6 DRUG EFFICACY AND TOXICITY 3.7 PHARMACOGENETICS 3.8 CONCLUSIONS ACKNOWLEDGMENT REFERENCES

11 4 ORGANIC ANION TRANSPORTERS (OATs) 4.1 OAT FAMILY 4.2 MOLECULAR CHARACTERIZATION 4.3 EXPRESSION AND REGULATION OF OATS 4.4 OAT SUBSTRATES AND DRUG–DRUG (DRUG–METABOLITE) INTERACTION 4.5 SYSTEMS BIOLOGY OF OATS 4.6 CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

12 5 ORGANIC ANION TRANSPORTING POLYPEPTIDES OATP 5.1 INTRODUCTION TO THE OATP SUPERFAMILY 5.2 MOLECULAR CHARACTERISTICS OF OATPS 5.3 EXPRESSION AND REGULATION OF OATPS 5.4 OATP SUBSTRATES, INHIBITORS, AND STIMULATORS 5.5 PHARMACOLOGY OF OATPS 5.6 PHYSIOLOGY AND PATHOPHYSIOLOGY OF OATPS 5.7 CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

13 6 MAMMALIAN OLIGOPEPTIDE TRANSPORTERS 6.1 INTRODUCTION 6.2 OLIGOPEPTIDE TRANSPORTERS 6.3 FUNCTIONAL PROPERTIES 6.4 REGULATION 6.5 PHARMACEUTICAL DRUG SCREENING 6.6 CONCLUDING REMARKS REFERENCES

14 7 MONOCARBOXYLIC ACID TRANSPORTERS 7.1 INTRODUCTION 7.2 SLC5 TRANSPORTER FAMILY 7.3 SLC16 TRANSPORTER FAMILY 7.4 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

15 8 THE NUCLEOSIDE TRANSPORTERS CNTs AND ENTs 8.1 INTRODUCTION 8.2 MOLECULAR AND FUNCTIONAL CHARACTERISTICS OF CNTs ( SLC28 ) 8.3 MOLECULAR AND FUNCTIONAL CHARACTERISTICS OF ENTs ( SLC29 ) 8.4 METHODS AND MOUSE MODELS TO STUDY ENTs AND CNTs 8.5 REGULATION OF CNTs AND ENTs 8.6 PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL FUNCTIONS OF CNTs AND ENTs 8.7 THERAPEUTIC SIGNIFICANCE OF CNTs AND ENTs 8.8 CONCLUSIONS ACKNOWLEDGMENT REFERENCES

16 9 BILE ACID TRANSPORTERS 9.1 INTRODUCTION 9.2 OVERVIEW OF TRANSPORTERS IN THE ENTEROHEPATIC CIRCULATION OF BILE ACIDS 9.3 HEPATOBILIARY BILE ACID TRANSPORTERS 9.4 INTESTINAL BILE ACID TRANSPORTERS 9.5 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

17 10 THE P‐GLYCOPROTEIN MULTIDRUG TRANSPORTER 10.1 MULTIDRUG RESISTANCE AND P‐GLYCOPROTEIN 10.2 EXPRESSION PATTERN OF P‐GLYCOPROTEIN 10.3 SUBSTRATES AND INHIBITORS OF P‐GLYCOPROTEIN 10.4 STRUCTURE OF P‐GLYCOPROTEIN 10.5 EPITOPE MAPPING OF MONOCLONAL ANTIBODIES SPECIFIC FOR HUMAN P‐GLYCOPROTEIN (MRK‐16, 4E3, AND UIC2) 10.6 MOLECULAR MECHANISM OF POLYSPECIFICITY 10.7 DRUG TRANSPORT CYCLE OF P‐GLYCOPROTEIN 10.8 EFFORTS TO DISCOVER MODULATORS 10.9 ROLE OF P‐GLYCOPROTEIN IN THE PHYSIOLOGY AND BIOAVAILABILITY OF DRUGS 10.10 CONCLUSIONS AND FUTURE PERSPECTIVE ACKNOWLEDGMENTS REFERENCES

18 11 MULTIDRUG RESISTANCE PROTEINS OF THE ABCC SUBFAMILY 11.1 INTRODUCTION 11.2 NOMENCLATURE AND MOLECULAR CHARACTERIZATION 11.3 EXPRESSION AND LOCALIZATION OF ABCC TRANSPORTERS IN NORMAL HUMAN TISSUES AND IN HUMAN CANCERS 11.4 FUNCTIONAL PROPERTIES/SUBSTRATE SPECIFICITY AND MULTIDRUG RESISTANCE PROFILES OF HUMAN ABCC/MRPS 11.5 CLINICAL CONSEQUENCES OF GENETIC VARIANTS IN ABCC GENES 11.6 CONCLUSION ACKNOWLEDGMENTS REFERENCES

19 12 ABCG2, THE BREAST CANCER RESISTANCE PROTEIN (BCRP) 12.1 DISCOVERY AND NOMENCLATURE 12.2 THE ABCG2 GENE AND EXPRESSION 12.3 PHYSICAL PROPERTIES 12.4 SUBSTRATES AND INHIBITORS OF BCRP 12.5 RECENT FINDINGS CONCERNING PHYSIOLOGICAL FUNCTIONS 12.6 PREDICTED PHYSIOLOGICAL FUNCTION FROM TISSUE DISTRIBUTION 12.7 ABCG2 EXPRESSION IN CANCER AND ITS ROLE IN DRUG RESISTANCE 12.8 GENETIC POLYMORPHISMS 12.9 CONCLUSION REFERENCES

20 13 DRUG TRANSPORT IN THE LIVER 13.1 INTRODUCTION 13.2 HEPATIC PHYSIOLOGY: LIVER STRUCTURE AND FUNCTION 13.3 HEPATIC TRANSPORT PROTEINS 13.4 REGULATION OF HEPATIC TRANSPORT PROTEINS IN HUMANS 13.5 PHYSIOLOGICAL FACTORS THAT INFLUENCE HEPATIC DRUG TRANSPORT PROTEINS IN HUMANS 13.6 DISEASE‐RELATED ALTERATIONS IN HUMAN HEPATIC TRANSPORT PROTEINS 13.7 METHODS FOR STUDYING HEPATOBILIARY DRUG TRANSPORT 13.8 HEPATIC TRANSPORTER‐MEDIATED DRUG–DRUG INTERACTIONS (DDIS) 13.9 INTERPLAY BETWEEN DRUG METABOLISM AND TRANSPORT 13.10 HEPATIC TRANSPORT PROTEINS AS DETERMINANTS OF DRUG TOXICITY 13.11 THE FUTURE OF HEPATIC DRUG TRANSPORT ACKNOWLEDGMENTS REFERENCES

21 14 DRUG TRANSPORT IN THE BRAIN 14.1 INTRODUCTION 14.2 PHYSIOLOGY OF THE BRAIN BARRIERS AND BRAIN PARENCHYMA 14.3 FUNCTIONAL EXPRESSION AND LOCALIZATION OF DRUG TRANSPORTERS IN THE BRAIN 14.4 RELEVANCE OF DRUG TRANSPORTERS IN CNS DISORDERS 14.5 CONCLUSION REFERENCES

22 15 DRUG TRANSPORT IN THE KIDNEY 15.1 KIDNEY STRUCTURE AND FUNCTION 15.2 MAJOR DRUG TRANSPORTERS EXPRESSED IN HUMAN KIDNEY 15.3 TARGETED PROTEOMICS OF HUMAN RENAL TRANSPORTERS 15.4 HUMAN TRANSPORTERS IN RENAL INJURY AND DISEASE 15.5 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

23 16 DRUG TRANSPORTERS IN THE HUMAN INTESTINE 16.1 INTRODUCTION 16.2 INTESTINAL ABC TRANSPORTERS (EXPRESSION, LOCALIZATION, FUNCTION) 16.3 INTESTINAL SLC TRANSPORTERS (EXPRESSION, LOCALIZATION, FUNCTION) 16.4 INTERPLAY OF APICAL AND BASOLATERAL TRANSPORTERS 16.5 VARIABILITY OF INTESTINAL TRANSPORTERS 16.6 DRUG–DRUG INTERACTIONS INVOLVING INTESTINAL TRANSPORTERS 16.7 LIMITATIONS OF AVAILABLE RESEARCH MODELS FOR THE HUMAN INTESTINE 16.8 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

24 17 DRUG TRANSPORT IN THE PLACENTA 17.1 INTRODUCTION 17.2 BLOOD–PLACENTAL BARRIER RELEVANT TO DRUG PERMEABILITY AND TRANSPORT 17.3 DRUG TRANSPORTERS IN HUMAN PLACENTA 17.4 METHODS TO STUDY PLACENTAL DRUG TRANSPORT 17.5 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

25 18 POLYMORPHISMS OF DRUG TRANSPORTERS AND CLINICAL RELEVANCE 18.1 INTRODUCTION 18.2 GENETIC VARIATION IN DRUG TRANSPORTERS LEADING TO ALTERED EFFECT 18.3 DISCUSSION 18.4 PERSPECTIVES REFERENCES

26 19 ONTOGENY OF DRUG TRANSPORTERS 19.1 INTRODUCTION 19.2 TRANSPORTER ONTOGENY 19.3 CHALLENGES IN ASSESSING TRANSPORTER ONTOGENY 19.4 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

27 20 EXPERIMENTAL APPROACHES FOR STUDYING DRUG TRANSPORTERS 20.1 INTRODUCTION 20.2 GENETICALLY MODIFIED AND HUMAN‐XENOGRAFT MODEL ANIMALS 20.3 IN VIVO EXPERIMENTS 20.4 ISOLATED TISSUE METHODS 20.5 PRIMARY CELL CULTURES, ESTABLISHED MODEL CELL LINES, AND THEIR COMBINATION 20.6 ANALYSIS OF THE TRANSPORT, INHIBITION, INDUCTION, AND DOWNREGULATION OF TRANSPORTERS 20.7 MEMBRANE VESICLES 20.8 PERSPECTIVES REFERENCES