Drug Transporters

28 21 TRANSPORTERS‐MEDIATED DRUG DISPOSITION—PHYSIOCHEMISTRY AND IN SILICO APPROACHES 21.1 INTRODUCTION 21.2 PHYSICOCHEMICAL DETERMINANTS OF HEPATOBILIARY TRANSPORT 21.3 IN SILICO MODELS FOR BILIARY ELIMINATION 21.4 PHYSICOCHEMICAL DETERMINANTS OF RENAL ELIMINATION 21.5 IN SILICO MODELS FOR RENAL ELIMINATION OR RENAL CLEARANCE 21.6 FRAMEWORK TO PREDICT TRANSPORTER‐MEDIATED CLEARANCE MECHANISM—EXTENDED CLEARANCE CLASSIFICATION SYSTEM (ECCS) 21.7 IN SILICO APPROACHES AND SAR OF CLINICALLY RELEVANT TRANSPORTERS 21.8 STRATEGIES TO ASSESS TRANSPORTER INVOLVEMENT DURING DRUG DISCOVERY 21.9 TARGETING DRUG TRANSPORTERS: CASE EXAMPLES 21.10 CONCLUSIONS REFERENCES

29 22 IN VITRO–IN VIVO SCALE‐UP OF DRUG TRANSPORT ACTIVITIES 22.1 INTRODUCTION 22.2 THEORETICAL BACKGROUND FOR THE PREDICTION OF IN VIVO PHARMACOKINETICS FROM IN VITRO DATA 22.3 PREDICTION OF HEPATIC TRANSPORT FROM IN VITRO DATA 22.4 PREDICTION OF RENAL TRANSPORT FROM IN VITRO DATA 22.5 PREDICTION OF TRANSPORTER‐MEDIATED DRUG–DRUG INTERACTIONS FROM IN VITRO DATA 22.6 CONCLUSIONS AND PERSPECTIVES REFERENCES

30 23 APPLICATION OF PHYSIOLOGICALLY BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODELING COMPRISING TRANSPORTERS 23.1 INTRODUCTION ‐ THE RISE OF PHYSIOLOGICALLY‐BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) APPLICATIONS IN INDUSTRY, ACADEMIA AND REGULATORY SPACE 23.2 MODELS AND THEIR ASSUMPTIONS 23.3 REAL‐WORLD APPLICATIONS OF TRANSPORTER ACTIVITY IN PBPK MODELS 23.4 CONCLUSIONS AND FUTURE PERSPECTIVES REFERENCES

31 24 TRANSPORTERS AS THERAPEUTIC TARGETS IN HUMAN DISEASES 24.1 INTRODUCTION 24.2 SLC TRANSPORTERS IN DISEASE AS TARGETS AND MODULATORS 24.3 ABC TRANSPORTERS IN DISEASE AS TARGETS AND MODULATORS 24.4 CONCLUSIONS AND FUTURE PERSPECTIVES ACKNOWLEDGMENTS REFERENCES

32 25 DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS 25.1 INTRODUCTION 25.2 DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS 25.3 CONCLUSIONS ACKNOWLEDGMENTS REFERENCES

33 INDEX

34 Wiley Series in Drug Discovery and Development

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1 Chapter 1 TABLE 1.1 Classifications of representative drug transporters

2 Chapter 2 TABLE 2.1 Tissue distribution of organic cation and zwitterion transporters... TABLE 2.2 Selected substrates and inhibitors of the major organic cation an... TABLE 2.3 Common missense variants of SLC22 family cation and zwitterion tr...

3 Chapter 3 TABLE 3.1 Prototypical and endogenous substrates of MATE transporters TABLE 3.2 Drug and metabolite substrates of MATE transporters TABLE 3.3 MATE1 and MATE2‐K substrates used in humans TABLE 3.4 MATE1 and MATE2‐K inhibitors identified in human studies TABLE 3.5 Human genetic variation in SLC47A1 and SLC47A2

4 Chapter 4 TABLE 4.1 OAT family members a TABLE 4.2 Characterization of Oat1/Oat3 knockout mice with respect to drugs...

5 Chapter 5 TABLE 5.1 Human OATPs and tissue expression a TABLE 5.2 Selected human OATP substrates, inhibitors, and stimulators a TABLE 5.3 Selected SLCO genetic variations, pharmacokinetics, and drug resp...

6 Chapter 6TABLE 6.1 A list of mammalian members of the POT family of transporters ado...TABLE 6.2 Summary of the molecular and functional characteristics of establ...

7 Chapter 7TABLE 7.1 Tissue and subcellular expression, substrate specificity, and inh...

8 Chapter 8TABLE 8.1 Molecular and functional characteristics of human nucleoside tran...TABLE 8.2 Apparent affinities (K m ) of various hCNTs and hENTs for adenos...

9 Chapter 10TABLE 10.1 P‐gp substrates and inhibitors a

10 Chapter 11TABLE 11.1 Nomenclature and properties of the human ABCC genes and ABCC pro...TABLE 11.2 Major sites of ABCC/MRP protein expression in normal human tissu...TABLE 11.3 Substrate and drug resistance profiles of human ABCC/MRP transpo...

11 Chapter 12TABLE 12.1 Select substrates and inhibitors of ABCG2TABLE 12.2 Summary of ABCG2 variants and their effects on transporter func...

12 Chapter 13TABLE 13.1 Human hepatic transporter alterations mediated by nuclear recept...TABLE 13.2 Examples of clinically relevant DDIs with hepatic transporter in...

13 Chapter 15TABLE 15.1 Major human SLC and ABC transporters expressed in renal proximal...

14 Chapter 16TABLE 16.1 Overview of transporter proteins in the human intestinal epithel...TABLE 16.2 Protein abundance of clinically relevant transporter proteins in...TABLE 16.3 Transcriptional regulation by nuclear receptors and epigenetic r...TABLE 16.4 Impact of different pathological conditions on the gene expressi...TABLE 16.5 Examples for clinically relevant drug‐drug interactions that can...

15 Chapter 18TABLE 18.1 Frequency of highlighted drug transporter polymorphisms in diffe...TABLE 18.2 Summary of impact of selected polymorphisms in genes encoding dr...

16 Chapter 19TABLE 19.1 Tissue‐specific maturation patterns for ABC transportersTABLE 19.2 Tissue‐specific maturation patterns for SLC transporters

17 Chapter 20TABLE 20.1 Experimental techniques used to study drug transporters

18 Chapter 22TABLE 22.1 Comparison of SHH and PHH for evaluation of hepatic uptake/efflu...TABLE 22.2 Reported inhibitors for which preincubation with cells potentiat...

19 Chapter 23TABLE 23.1 Common problems in deriving key parameters in Transporter IVIVE‐...TABLE 23.2 Archetypal transporter‐IVIVE scalars, with their incorporation in...

20 Chapter 24TABLE 24.1 SLC transporters as targets in diseaseTABLE 24.2 ABC transporters as targets in disease

21 Chapter 25TABLE 25.1 Effects of dietary supplements on drug transportersTABLE 25.2 Chemical structures of subclasses of flavonoidsTABLE 25.3 Interactions of flavonoids with P‐gpTABLE 25.4 Interactions of flavonoids with MRPsTABLE 25.5 Interactions of flavonoids with BCRPTABLE 25.6 Interactions of flavonoids with OATPsTABLE 25.7 Interactions of isothiocyanates with transporters

1 Chapter 2 FIGURE 2.1 Tissue distribution and membrane localization of organic cation a... FIGURE 2.2 (a) Alternating‐access transport model for translocation of subst... FIGURE 2.3 Predicted secondary structure of OCT1 with most common (GAF > 0.0...

2 Chapter 3 FIGURE 3.1 Mate transporters across species and localization. (a) Phylogenic... FIGURE 3.2 Examples of MATE inhibitors. Structures of chemical inhibitors we... FIGURE 3.3 Predicted structure of the human MATE1 transporter. The membrane ...

3 Chapter 4 FIGURE 4.1 Schematic illustrating the transmembrane topology of organic anio... FIGURE 4.2 Post‐translational modifications of OATs.Ubiquitination an... FIGURE 4.3 ABC and SLC transporters contribute to remote sensing and signali...

4 Chapter 6FIGURE 6.1 This schematic illustrates the potential parallel/competing pathw...FIGURE 6.2 The effective permeability of the physiological barrier is a func...FIGURE 6.3 This schematic demonstrates the potential pathways of saquinavir ...