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Drug Transporters
Molecular Characterization and Role in Drug Disposition
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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


PRODUCT DETAILS

ISBN-13: 9781118705049
Publisher: John Wiley & Sons Ltd (Wiley–Blackwell)
Publication date: October, 2014
Pages: 528
Dimensions: 217.00 x 286.00 x 31.73

Subcategories: Pharmacology

MEET THE AUTHOR

Guofeng You is a Distinguished Professor of Pharmaceuticsin the Ernest Mario School of Pharmacy at Rutgers University, USA.She has published numerous original research articles in the fieldof drug transport. She has been serving on several grant reviewpanels of the National Institutes of Health and is on the editorialboards of leading journals. She was the coeditor for the firstedition of this book (Wiley, 2007).


Marilyn E. Morris is Professor in the Department ofPharmaceutical Sciences  at the University at Buffalo, StateUniversity of New York. She is a Fellow of the American Associationof Pharmaceutical Scientists (AAPS) and the American Associationfor the Advancement of Science (AAAS). and currently serves on theeditorial boards of leading journals and was also co–editor for thefirst edition of this book (Wiley, 2007).