Drug Transporters (eBook)

Preface 6
Reference 7
Contents 8
Contributors 10
Uptake Transporters of the Human OATP Family 12
1 Introduction 13
2 The Human OATP Family 14
2.1 Molecular Characteristics of Human OATP Family Members 14
2.2 Substrate Spectrum of Human OATP Family Members 19
2.3 Hepatic OATPs and Drug–Drug Interactions 22
2.4 Functional Consequences of Genetic Variations in Transporter Genes 26
2.4.1 Pharmacogenomics of OATP1B1 26
2.4.2 Pharmacogenomics of Other Human OATP Family Members 30
3 Conclusions 32
References 33
In Vitro and In Vivo Evidence of the Importance of Organic Anion Transporters (OATs) in Drug Therapy 40
1 Organic Anion Transporters Within the SLC22A Gene Family 42
2 Organic Anion Transporter 1 (OAT1/Oat1 Gene name SLC22A6/Slc22a6)43
2.1 Cloning, Structure 43
2.2 Tissue Distribution of mRNA 45
2.3 Immunolocalization of OAT1/Oat1 Protein 47
2.4 Species Differences, Age and Gender Dependence of Expression 47
2.5 Factors Influencing Activity and Abundance of OAT1/Oat1 48
2.6 Substrates 50
2.6.1 Endogenous Substrates of OAT1/Oat1 51
2.6.2 Drugs 53
2.7 Inhibitors 60
2.8 Drug/Drug Interactions 61
2.9 Pharmacogenomics 62
3 Organic Anion Transporter 2 (OAT2/Oat2, Gene Name SLC22A7/Slc22a7) 63
3.1 Cloning, Structure 63
3.2 Tissue Distribution of mRNA 63
3.3 Immunolocalization of OAT2/Oat2 Protein 64
3.4 Species Differences, Age and Gender Dependence of Expression 64
3.5 Factors Influencing Activity and Abundance of OAT2/Oat2 65
3.6 Substrates 65
3.6.1 Endogenous Substrates 66
3.6.2 Drugs 66
3.7 Inhibitors 69
3.8 Drug/Drug Interactions 69
3.9 Pharmacogenomics 69
4 Organic Anion Transporter 3 (OAT3/Oat3, Gene Name SLC22A8/Slc22a8) 69
4.1 Cloning, Structure 69
4.2 Tissue Distribution of mRNA 70
4.3 Immunolocalization of OAT3/Oat3 Protein 70
4.4 Species Differences, Age and Gender Dependence of Expression 71
4.5 Factors Influencing Activity and Abundance of OAT3/Oat3 71
4.6 Substrates 72
4.6.1 Endogenous Substrates 73
4.6.2 Drugs 75
4.7 Inhibitors 80
4.8 Drug/Drug Interactions 80
4.9 Pharmacogenomics 82
5 Organic Anion Transporter 4 (OAT4, Gene Name SLC22A11) 82
5.1 Cloning, Structure 82
5.2 Tissue Distribution of mRNA 83
5.3 Immunolocalization of OAT4 Protein 83
5.4 Species Differences, Age and Gender Dependence of Expression 84
5.5 Factors Influencing Activity and Abundance of OAT4 84
5.6 Substrates 84
5.6.1 Endogeneous Substrates 84
5.6.2 Drugs 85
5.7 Inhibitors 89
5.8 Drug/Drug Interactions 89
5.9 Pharmacogenomics 89
6 Urate Transporter 1 (URAT1 Urat1/Rst, Gene Name SLC22A12/Slc22a12)89
6.1 Cloning, Structure 89
6.2 Tissue Distribution of mRNA 90
6.3 Immunolocalization of URAT1/Urat1/Rst Protein 90
6.4 Species Differences, Age and Gender Dependence of Expression 91
6.5 Factors Influencing Activity and Abundance of URAT1/Urat1/Rst 91
6.6 Substrates 91
6.6.1 Endogenous Substrates 92
6.6.2 Drugs 92
6.7 Inhibitors 93
6.8 Drug/Drug Interactions 93
6.9 Pharmacogenomics 94
7 Organic Anion Transporter 10 (OAT10/ORCTL3, Gene Name SLC22A13) 94
7.1 Cloning, Structure 94
7.2 Tissue Distribution of mRNA 94
7.3 Immunolocalization of OAT10 Protein, Gender Differences 95
7.4 Substrates 95
7.4.1 Endogenous Substrates (Bahn et al. 2008) 95
7.4.2 Drugs (Bahn et al. 2008) 96
7.5 Inhibitors, Drug/Drug Interactions, Pharmacogenomics 96
8 Organic Anion Transporter 5 (Oat5, Gene Name Slc22a19) 96
8.1 Cloning, Structure 96
8.2 Tissue Distribution of mRNA, Immunolocalization, Gender Differences 96
8.3 Substrates 97
8.3.1 Endogenous Substrates 97
8.3.2 Drugs (Rat Oat5: Anzai et al. 2005 Mouse Oat5: Youngblood and Sweet 2004)97
8.4 Inhibitors, Drug/Drug Interactions, Pharmacogenomics 97
9 Organic Anion Transporter 6 (Oat6, Gene Name Slc22a20) 98
9.1 Cloning, Structure, Tissue Distribution 98
9.2 Species Differences, Age and Gender Dependence of Expression Abundance98
9.3 Substrates 98
9.3.1 Endogenous Substrates 98
9.3.2 Drugs 99
9.4 Inhibitors 99
9.5 Drug/Drug Interactions: Pharmacogenomics 99
10 Organic Anion Transporter 7 (OAT7, Gene Name SLC22A9) 100
10.1 Cloning, Structure, Tissue Distribution, Localization 100
10.2 Substrates (Shin et al. 2007) 100
11 Organic Anion Transporter 8 (Oat8, Gene Name Slc22a9) 100
11.1 Cloning, Structure, Tissue Distribution, Localization 100
11.2 Substrates (Yokoyama et al. 2008) 101
12 Organic Anion Transporter 9 (Oat9, Gene Name Unknown) 101
12.1 Cloning, Tissue Distribution, Substrates 101
References 101
Organic Cation Transporters (OCTs, MATEs), In Vitro and In Vivo Evidence for the Importance in Drug Therapy 116
1 Introduction 117
2 Cloning and Molecular Characterization of OCT and MATE Transporters 119
2.1 OCT Transporters 119
2.2 MATE Transporters 136
3 Tissue Distribution and Subcellular Localization 136
3.1 OCT1 137
3.2 OCT2 137
3.3 OCT3 139
3.4 MATE1 and MATE2-K 139
4 Functional Characterization of OCT and MATE Transporters 139
4.1 Common Functional Properties of OCTs 139
4.2 Substrate and Inhibitor Specificities of Human OCTs 140
4.3 Drug-Drug Interactions Involving OCTs 141
4.4 Common Functional Properties of MATEs 142
4.5 Substrate and Inhibitor Specificities of MATEs 142
4.6 Drug-Drug Interactions Involving MATEs 142
5 Knockout Mouse Models 143
5.1 Oct1 Knockout Mice 143
5.2 Oct2 Single-Knockout and Oct1/Oct2 Double-Knockout Mice 144
5.3 Oct3 Knockout Mice 144
5.4 Mate1 Knockout Mice 145
6 Pharmacogenomics of OCT and MATE Transporters 145
6.1 Identification of Genetic Variants, Their Predicted Consequences, and Their Effects In Vitro 145
6.2 Interethnic Variability 146
6.3 Phenotype–Genotype Correlations 151
References 168
Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition 179
1 Overview of the Enterohepatic Circulation of Bile Acids 181
2 Overview of Intestinal Bile Acid Transport 182
3 The Apical Sodium-Dependent Bile Acid Transporter: ASBT 182
3.1 ASBT General Properties and Tissue Expression 182
3.2 ASBT Structure 186
3.3 ASBT Structure–Function Relationships 188
3.4 ASBT Substrate Specificity and Native Bile Acid Pharmacophore Models 189
3.5 ASBT Genomics and Pathophysiology 190
4 The Basolateral Bile Acid and Organic Solute Transporter: OSTa–OSTß 193
4.1 OSTa–OSTß General Properties and Tissue Expression 193
4.2 OSTa–OSTß Genomics and Pathophysiology 195
5 Development of ASBT Inhibitors 195
6 Targeting the ASBT for Prodrug Delivery 198
7 Role of the Intestinal Bile Acid Transporters in Drug Absorption and Drug Interactions 200
7.1 Role of ASBT in Drug Absorption and Drug Interactions 200
7.2 Role of OSTa–OSTß in Drug Absorption and Drug Interactions 201
References 203
The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of BileFormation 214
1 Physiology of Bile Formation 215
2 The Sodium Taurocholate Cotransporting Polypeptide Ntcp/NTCP 217
2.1 Molecular Properties 217
2.2 Subcellular Expression and Tissue Distribution 218
2.3 Phylogenetics and Ontogenesis 219
2.4 Transport Properties 219
2.5 NTCP/Ntcp Inhibitors 222
2.6 Pathophysiology 225
2.7 Pharmacogenomics 226
3 The Bile Salt Export Pump Bsep/BSEP 227
3.1 Molecular Properties 227
3.2 Subcellular Expression and Tissue Distribution 228
3.3 Phylogenetics and Ontogenesis 229
3.4 Transport Properties 230
3.5 BSEp/bSEP Inhibitors 233
3.6 Pathophysiology 238
3.7 Mutations in the BSEP Gene 241
3.8 Pharmacogenomics of BSEP 243
3.9 In Vitro Characterization of BSEP Variants and Animal Models for Altered Bsep Expression 245
4 Conclusion 248
References 249
P-glycoprotein: Tissue Distribution, Substrates, and Functional Consequences of Genetic Variations 269
1 Introduction 270
2 Tissue Distribution 271
2.1 Intestine 271
2.2 Liver 271
2.3 Kidney 272
2.4 Blood–Brain Barrier 272
2.5 Placenta 272
2.6 Lymphocytes 273
3 Substrates 273
4 ABCB1 Genetic Polymorphisms 274
4.1 Functional Consequences of Genetic Variations 274
4.2 Association to Drug Bioavailability 275
4.2.1 Digoxin 277
4.2.2 Talinolol 278
4.2.3 Antihistaminics 278
4.2.4 Protease Inhibitors 278
4.2.5 Anticonvulsants 279
4.2.6 Immunosuppressants 281
4.2.7 Cytostatics 282
5 Conclusion 283
References 283
Importance of P-glycoprotein for Drug–Drug Interactions 292
1 Induction of P-glycoprotein 293
2 Inhibition of P-glycoprotein 296
3 Summary 301
References 301
Multidrug Resistance Proteins (MRPs, ABCCs): Importance for Pathophysiology and Drug Therapy 305
1 Introduction 306
2 Tissue Distribution and Cellular Localization of Multidrug Resistance Proteins of the ABCC Subfamily 308
2.1 MRP1 Localization 308
2.2 MRP2 Localization 309
2.3 MRP3 Localization 309
2.4 MRP4 Localization 310
2.5 MRP5 Localization 310
2.6 MRP6 Localization 310
2.7 MRP7–9 (ABCC10–12) Localization 311
3 Substrates of Multidrug Resistance Proteins of the ABCC Subfamily 311
3.1 MRP1 Substrates 314
3.2 MRP2 Substrates 314
3.3 MRP3 Substrates 315
3.4 MRP4 Substrates 315
3.5 MRP5 Substrates 316
3.6 MRP6 Substrates 316
3.7 Substrates for MRP7, MRP8, MRP9 317
4 Inhibitors of Multidrug Resistance Proteins of the ABCC Subfamily 317
5 Genetic Variants, Knockout Animals, and Disease 319
References 322
In Vitro and In Vivo Evidence for the Importance of Breast Cancer Resistance Protein Transporters (BCRP/MXR/ABCP/ABCG2) 330
1 ABCG2 Tissue Distribution 334
2 ABCG2 Substrates and Inhibitors 334
3 Abcg2 Function In Vivo: Data from Mouse Models 337
3.1 Abcg2 and Oral Bioavailability 338
3.2 Abcg2 and Biliary Excretion 339
3.3 Abcg2 and the Blood–Brain Barrier 340
3.4 Abcg2 in the Feto-Maternal Barrier 342
3.5 Abcg2 in the Lactating Mammary Gland 342
4 ABCG2 a Contributor to Multidrug Resistance 343
5 ABCG2 a Marker of Cancer Stem Cells 345
6 Side Population Phenotype in Stem Cells is Determined by ABCG2 Expression and Activity 346
7 Pharmacogenomics of ABCG2 347
8 ABCG2 a Risk Factor for Gout 352
9 Summary 356
References 356
Molecular Mechanisms of Drug Transporter Regulation 377
1 Introduction 378
2 Transcriptional Regulation of Drug Transporters 381
2.1 Nuclear Receptor Signaling 381
2.1.1 Pregnane X Receptor 382
2.1.2 Constitutive Androstane Receptor 383
2.1.3 Farnesoid X Receptor 383
2.1.4 Vitamin D Receptor 384
2.2 Drug Transporters Regulated by Nuclear Receptors 384
2.2.1 MDR1 P-gp 384
2.2.2 Multidrug Resistance-Associated Proteins 385
2.2.3 Breast Cancer Resistance Protein 385
2.2.4 Bile Salt Export Pump 386
2.2.5 Organic Anion Transporting Polypeptides 386
2.2.6 Sodium-Taurocholate Cotransporting Polypeptide 387
2.2.7 Organic Solute Transporter a/ß 387
2.3 Nuclear Receptor Splice Variants and Drug Transporter Expression 387
2.4 Nuclear Receptor Antagonism and Impact on Drug Transporters 388
2.5 In Vitro and Animal Models of Drug Transporter Transcriptional Regulation 388
3 Therapeutic Aspects of Drug Transporter Regulation 390
3.1 Drug–Drug Interactions Involving Drug Transporter Regulation 390
3.2 Nuclear Receptor Pharmacogenetics and Drug Transporter Expression 390
3.3 Xenobiotic Receptors as Drug Targets: Implications for Drug Transporter Expression 392
4 Perspectives 393
References 394
In Vivo Probes of Drug Transport: Commonly Used Probe Drugs to Assess Function of Intestinal P-glycoprotein (ABCB1) in Humans 407
1 Introduction 408
1.1 Expression, Function and Variability of Intestinal P-glycoprotein in Man 408
1.2 Criteria for an In Vivo Probe Drug of Intestinal P-glycoprotein 410
2 Digoxin 412
2.1 Safety, Physicochemical Properties and Pharmacokinetics 412
2.2 Affinity to P-glycoprotein In Vitro and in Animal Studies 412
2.3 Evidence from Mechanistic Clinical Studies 415
2.4 Digoxin Disposition and Induction of Intestinal P-glycoprotein 416
2.5 Digoxin Disposition and Inhibition of Intestinal P-glycoprotein 417
2.6 Regioselective Absorption of Digoxin 421
2.7 Digoxin as a Probe Drug for Genetic Polymorphisms of P-glycoprotein 421
2.8 Limitations of Digoxin 424
3 Talinolol 427
3.1 Safety, Physicochemical Properties and Pharmacokinetics 427
3.2 Affinity to P-glycoprotein In Vitro and in Animal Studies 428
3.3 Evidence from Mechanistic Clinical Studies 431
3.4 Talinolol Disposition and Induction of Intestinal P-glycoprotein 432
3.5 Talinolol Disposition and Inhibition of Intestinal P-glycoprotein 433
3.6 Regioselective Absorption of Talinolol 433
3.7 Talinolol as a Probe Drug for Genetic Polymorphisms of P-glycoprotein 434
3.8 Limitations of the Application of Talinolol as a Probe Drug 434
4 Conclusions and Recommendations 436
4.1 Selectivity for Intestinal P-glycoprotein 436
4.2 Limitations Resulting from Intestinal Uptake Mechanisms 437
4.3 Safety and Methodological Issues 438
References 439
Index 452