Drug Transporters (Handbook of Experimental Pharmacology, Volume 201)

Drug Transporters (Handbook of Experimental Pharmacology, Volume 201)......Page 1
Front-matter......Page 2
Drug Transporters......Page 4
Copyright......Page 5
Preface......Page 6
Reference......Page 7
Contents......Page 8
Contributors......Page 10
Uptake Transporters of the Human OATP Family......Page 12
1 Introduction......Page 13
2.1 Molecular Characteristics of Human OATP Family Members......Page 14
2.2 Substrate Spectrum of Human OATP Family Members......Page 19
I2.3 Hepatic OATPs and Drug–Drug Interactions......Page 22
2.4.1 Pharmacogenomics of OATP1B1......Page 26
2.4.2 Pharmacogenomics of Other Human OATP Family Members......Page 30
3 Conclusions......Page 32
References......Page 33
In Vitro and In Vivo Evidence of the Importance of Organic Anion Transporters (OATs) in Drug Therapy......Page 40
1 Organic Anion Transporters Within the SLC22A Gene Family......Page 42
2.1 Cloning, Structure......Page 43
2.2 Tissue Distribution of mRNA......Page 45
2.4 Species Differences, Age and Gender Dependence of Expression......Page 47
2.5 Factors Influencing Activity and Abundance of OAT1/Oat1......Page 48
2.6 Substrates......Page 50
2.6.1 Endogenous Substrates of OAT1/Oat1......Page 51
2.6.2 Drugs......Page 53
2.7 Inhibitors......Page 60
2.8 Drug/Drug Interactions......Page 61
2.9 Pharmacogenomics......Page 62
3.2 Tissue Distribution of mRNA......Page 63
3.4 Species Differences, Age and Gender Dependence of Expression......Page 64
3.6 Substrates......Page 65
3.6.2 Drugs......Page 66
4.1 Cloning, Structure......Page 69
4.3 Immunolocalization of OAT3/Oat3 Protein......Page 70
4.5 Factors Influencing Activity and Abundance of OAT3/Oat3......Page 71
4.6 Substrates......Page 72
4.6.1 Endogenous Substrates......Page 73
4.6.2 Drugs......Page 75
4.8 Drug/Drug Interactions......Page 80
5.1 Cloning, Structure......Page 82
5.3 Immunolocalization of OAT4 Protein......Page 83
5.6.1 Endogeneous Substrates......Page 84
5.6.2 Drugs......Page 85
6.1 Cloning, Structure......Page 89
6.3 Immunolocalization of URAT1/Urat1/Rst Protein......Page 90
6.6 Substrates......Page 91
6.6.2 Drugs......Page 92
6.8 Drug/Drug Interactions......Page 93
7.2 Tissue Distribution of mRNA......Page 94
7.4.1 Endogenous Substrates (Bahn et al. 2008)......Page 95
8.2 Tissue Distribution of mRNA, Immunolocalization, Gender Differences......Page 96
8.4 Inhibitors, Drug/Drug Interactions, Pharmacogenomics......Page 97
9.3.1 Endogenous Substrates......Page 98
9.5 Drug/Drug Interactions: Pharmacogenomics......Page 99
11.1 Cloning, Structure, Tissue Distribution, Localization......Page 100
References......Page 101
Organic Cation Transporters (OCTs, MATEs), In Vitro and In Vivo Evidence for the Importance in Drug Therapy......Page 116
1 Introduction......Page 117
2.1 OCT Transporters......Page 119
3 Tissue Distribution and Subcellular Localization......Page 136
3.2 OCT2......Page 137
4.1 Common Functional Properties of OCTs......Page 139
4.2 Substrate and Inhibitor Specificities of Human OCTs......Page 140
4.3 Drug-Drug Interactions Involving OCTs......Page 141
4.6 Drug-Drug Interactions Involving MATEs......Page 142
5.1 Oct1 Knockout Mice......Page 143
5.3 Oct3 Knockout Mice......Page 144
6.1 Identification of Genetic Variants, Their Predicted Consequences, and Their Effects In Vitro......Page 145
6.2 Interethnic Variability......Page 146
6.3 Phenotype-Genotype Correlations......Page 151
References......Page 168
Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition......Page 180
1 Overview of the Enterohepatic Circulation of Bile Acids......Page 182
3.1 ASBT General Properties and Tissue Expression......Page 183
3.2 ASBT Structure......Page 187
3.3 ASBT Structure–Function Relationships......Page 189
3.4 ASBT Substrate Specificity and Native Bile Acid Pharmacophore Models......Page 190
3.5 ASBT Genomics and Pathophysiology......Page 191
4.1 OSTα–OSTβ General Properties and Tissue Expression......Page 194
5 Development of ASBT Inhibitors......Page 196
6 Targeting the ASBT for Prodrug Delivery......Page 199
7.1 Role of ASBT in Drug Absorption and Drug Interactions......Page 201
7.2 Role of OSTα–OSTβ in Drug Absorption and Drug Interactions......Page 202
References......Page 204
The Role of the Sodium-Taurocholate Cotransporting Polypeptide (NTCP) and of the Bile Salt Export Pump (BSEP) in Physiology and Pathophysiology of Bile Formation......Page 216
1 Physiology of Bile Formation......Page 217
2.1 Molecular Properties......Page 219
2.2 Subcellular Expression and Tissue Distribution......Page 220
2.4 Transport Properties......Page 221
2.5 NTCP/Ntcp Inhibitors......Page 224
2.6 Pathophysiology......Page 227
2.7 Pharmacogenomics......Page 228
3.1 Molecular Properties......Page 229
3.2 Subcellular Expression and Tissue Distribution......Page 230
3.3 Phylogenetics and Ontogenesis......Page 231
3.4 Transport Properties......Page 232
3.5 BSEp/bSEP Inhibitors......Page 235
3.6 Pathophysiology......Page 240
3.7 Mutations in the BSEP Gene......Page 243
3.8 Pharmacogenomics of BSEP......Page 245
3.9 In Vitro Characterization of BSEP Variants and Animal Models for Altered Bsep Expression......Page 247
4 Conclusion......Page 250
References......Page 251
P-glycoprotein: Tissue Distribution, Substrates, and Functional Consequences of Genetic Variations......Page 272
1 Introduction......Page 273
2.2 Liver......Page 274
2.5 Placenta......Page 275
3 Substrates......Page 276
4.1 Functional Consequences of Genetic Variations......Page 277
4.2 Association to Drug Bioavailability......Page 278
4.2.1 Digoxin......Page 280
4.2.4 Protease Inhibitors......Page 281
4.2.5 Anticonvulsants......Page 282
4.2.6 Immunosuppressants......Page 284
4.2.7 Cytostatics......Page 285
References......Page 286
Importance of P-glycoprotein for Drug–Drug Interactions......Page 296
1 Induction of P-glycoprotein......Page 297
2 Inhibition of P-glycoprotein......Page 300
References......Page 305
Multidrug Resistance Proteins (MRPs, ABCCs): Importance for Pathophysiology and Drug Therapy......Page 310
1 Introduction......Page 311
2.1 MRP1 Localization......Page 313
2.3 MRP3 Localization......Page 314
2.6 MRP6 Localization......Page 315
3 Substrates of Multidrug Resistance Proteins of the ABCC Subfamily......Page 316
3.2 MRP2 Substrates......Page 319
3.4 MRP4 Substrates......Page 320
3.6 MRP6 Substrates......Page 321
4 Inhibitors of Multidrug Resistance Proteins of the ABCC Subfamily......Page 322
5 Genetic Variants, Knockout Animals, and Disease......Page 324
References......Page 327
In Vitro and In Vivo Evidence for the Importance of Breast Cancer Resistance Protein Transporters (BCRP/MXR/ABCP/ABCG2)......Page 336
2 ABCG2 Substrates and Inhibitors......Page 340
3 Abcg2 Function In Vivo: Data from Mouse Models......Page 343
3.1 Abcg2 and Oral Bioavailability......Page 344
3.2 Abcg2 and Biliary Excretion......Page 345
3.3 Abcg2 and the Blood–Brain Barrier......Page 346
3.5 Abcg2 in the Lactating Mammary Gland......Page 348
4 ABCG2 a Contributor to Multidrug Resistance......Page 349
5 ABCG2 a Marker of Cancer Stem Cells......Page 351
6 Side Population Phenotype in Stem Cells is Determined by ABCG2 Expression and Activity......Page 352
7 Pharmacogenomics of ABCG2......Page 353
8 ABCG2 a Risk Factor for Gout......Page 358
References......Page 362
Molecular Mechanisms of Drug Transporter Regulation......Page 384
1 Introduction......Page 385
2.1 Nuclear Receptor Signaling......Page 388
2.1.1 Pregnane X Receptor......Page 389
2.1.3 Farnesoid X Receptor......Page 390
2.2.1 MDR1 P-gp......Page 391
2.2.3 Breast Cancer Resistance Protein......Page 392
2.2.5 Organic Anion Transporting Polypeptides......Page 393
2.3 Nuclear Receptor Splice Variants and Drug Transporter Expression......Page 394
2.5 In Vitro and Animal Models of Drug Transporter Transcriptional Regulation......Page 395
3.2 Nuclear Receptor Pharmacogenetics and Drug Transporter Expression......Page 397
3.3 Xenobiotic Receptors as Drug Targets: Implications for Drug Transporter Expression......Page 399
4 Perspectives......Page 400
References......Page 401
In Vivo Probes of Drug Transport: Commonly Used Probe Drugs to Assess Function of Intestinal P-glycoprotein (ABCB1) in Humans......Page 414
1.1 Expression, Function and Variability of Intestinal P-glycoprotein in Man......Page 415
1.2 Criteria for an In Vivo Probe Drug of Intestinal P-glycoprotein......Page 417
2.2 Affinity to P-glycoprotein In Vitro and in Animal Studies......Page 419
2.3 Evidence from Mechanistic Clinical Studies......Page 422
2.4 Digoxin Disposition and Induction of Intestinal P-glycoprotein......Page 423
2.5 Digoxin Disposition and Inhibition of Intestinal P-glycoprotein......Page 424
2.7 Digoxin as a Probe Drug for Genetic Polymorphisms of P-glycoprotein......Page 428
2.8 Limitations of Digoxin......Page 431
3.1 Safety, Physicochemical Properties and Pharmacokinetics......Page 434
3.2 Affinity to P-glycoprotein In Vitro and in Animal Studies......Page 435
3.3 Evidence from Mechanistic Clinical Studies......Page 438
3.4 Talinolol Disposition and Induction of Intestinal P-glycoprotein......Page 439
3.6 Regioselective Absorption of Talinolol......Page 440
3.8 Limitations of the Application of Talinolol as a Probe Drug......Page 441
4.1 Selectivity for Intestinal P-glycoprotein......Page 443
4.2 Limitations Resulting from Intestinal Uptake Mechanisms......Page 444
4.3 Safety and Methodological Issues......Page 445
References......Page 446
Index......Page 460