Drug Transporters E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Wiley series in drug discovery and development
• Sprache: Englisch

Seitenzahl: 1768

Veröffentlichungsjahr: 2014

Beschreibung

This new edition overviews drug transporters and presents the principles of drug transport and associated techniques, featuring new chapters on multidrug and toxin extrusion proteins, placental transport, in silico approaches in drug discovery, and regulatory guidance for drug transport studies in drug development. * Describes drug transporter families, mechanisms, and clinical implications along with experimental methods for studying and characterizing drug transporters * Includes new chapters on multidrug and toxin extrusion proteins, placental transport and in silico approaches in drug discovery * Has a new chapter covering regulatory guidance for the evaluation of drug transport in drug development with global criteria used for drug transporters in clinical trials * Arranges material to go from fundamental mechanisms to clinical outcomes, making the book useful for novice and expert readers

Leseprobe

CONTENTS

Cover

Wiley Series in Drug Discovery and Development

Title page

Copyright page

Dedication page

Preface to the Second Edition

Preface to the First Edition

List of Contributors

1 Overview of Drug Transporter Families

1.1 What Are Drug Transporters?

1.2 Structure and Model of Drug Transporters

1.3 Transport Mechanisms

1.4 Polarized Expression of Drug Transporters in Barrier Epithelium

1.5 Classifications of Drug Transporters

1.6 Regulation of Drug Transporters

References

2 Organic Cation and Zwitterion Transporters (OCTs, OCTNs)

2.1 Introduction

2.2 hOCT1 (

SLC22A1

), hOCT2 (

SLC22A2

), and hOCT3 (

SLC22A3

)

2.3 hOCTN1 (

SLC22A4

) and hOCTN2 (

SLC22A5

)

2.4 hOCT6 (

SLC22A16

)

2.5 Conclusions

References

3 Organic Anion Transporters

3.1 OAT Family

3.2 Molecular Characterization

3.3 Expression and Regulation of OATs

3.4 OAT Substrates

3.5 Systems Biology of OATs

3.6 Conclusions

Acknowledgments

References

4 Organic Anion-Transporting Polypeptides

4.1 Introduction to the OATP Superfamily

4.2 Molecular Characteristics of OATPs

4.3 Expression and Regulation of OATPs

4.4 OATP Substrates and Inhibitors

4.5 Pharmacology of OATPs

4.6 Physiological/Pathophysiological Roles

4.7 Conclusions

Acknowledgments

References

5 Peptide Transporters

5.1 Introduction

5.2 Molecular and Structural Characteristics

5.3 Functional Properties

5.4 Regulation

5.5 Pharmaceutical Drug Screening

5.6 Concluding Remarks

Acknowledgments

References

6 Monocarboxylic Acid Transporters

6.1 Introduction

6.2 Mitochondrial Pyruvate Transporter Family

6.3 SLC5 Transporter Family

6.4 SLC16 Transporter Family

References

7 The Nucleoside Transporters CNTs and ENTs

7.1 Introduction

7.2 Molecular and Functional Characteristics of CNTs (SLC28)

7.3 Molecular and Functional Characteristics of ENTs (SLC29)

7.4 Regulation of CNT and ENT Nucleoside Transporters

7.5 Physiological and Pathophysiological Functions of CNTs AND ENTs

7.6 Therapeutic Significance of CNTs and ENTs

7.7 Conclusions and Future Directions

Acknowledgment

Abbreviations

References

8 Bile Salt Transporters

8.1 Overview of the Enterohepatic Circulation of Bile Salts

8.2 The Chief Transporters in the Enterohepatic Circulation of Bile Salts

8.3 Enterohepatic Bile Salt Transporters in Liver Disease

8.4 Control of Bile Salt Transport and Metabolism

8.5 Nuclear Receptors as Transcriptional Regulators of Bile Salt Homeostasis

8.6 FXR-Dependent Mechanisms That Regulate Human Bile Salt Transporter Genes

8.7 Cross Talk between the Transcriptional Control of Bile Salt and Drug Transporters

8.8 Concluding Remarks and Future Perspectives

References

9 Multidrug Resistance Protein: P-Glycoprotein

9.1 The P-Glycoprotein Gene Family

9.2 Tissue Distribution of P-Glycoprotein

9.3 Role of P-Glycoprotein in Human Physiology

9.4 P-Glycoprotein Substrates and Modulators

9.5 P-Glycoprotein Structure

9.6 Subcellular Systems for Studying P-Glycoprotein

9.7 ATP Binding and Hydrolysis by P-Glycoprotein

9.8 Drug Binding by P-Glycoprotein

9.9 P-Glycoprotein-Mediated Drug Transport

9.10 Substrate Specificity of P-Glycoprotein and the Nature of the Drug-Binding Site

9.11 P-Glycoprotein as a Hydrophobic Vacuum Cleaner or Drug Flippase

9.12 Role of the Lipid Bilayer in P-Glycoprotein Function

9.13 Mechanism of Action of P-Glycoprotein

9.14 Role of P-Glycoprotein in Drug Therapy

9.15 Modulation of P-Glycoprotein in Cancer Treatment

9.16 Regulation of P-Glycoprotein Expression

9.17 P-Glycoprotein Gene Polymorphisms and Their Implications in Drug Therapy and Disease

9.18 Summary and Conclusions

References

10 Multidrug Resistance Proteins of the ABCC Subfamily

10.1 Introduction

10.2 Molecular Characteristics

10.3 Functional Properties, Substrate Specificity, and Multidrug Resistance Profiles of Human ABCC/MRPs

10.4 Localization of ABCC/MRP Efflux Transporters in Normal Human Tissues and in Human Cancers

10.5 Genotype–Phenotype Correlations and Clinical Consequences of Genetic Variants in

ABCC

Genes

10.6 Conclusions and Future Prospects

Acknowledgments

References

11 Breast Cancer Resistance Protein (BCRP) or ABCG2

11.1 Discovery and Nomenclature

11.2

ABCG2

Gene and Expression

11.3 Physical Properties

11.4 Substrates/Inhibitors of ABCG2

11.5 Recent Findings in Physiological Function

11.6 Predicted Physiological Function from Tissue Distribution

11.7 ABCG2 Expression in Cancer and Its Role in Drug Resistance

11.8 Genetic Polymorphisms

11.9 Conclusion

References

12 Multidrug and Toxin Extrusion Proteins

12.1 Introduction

12.2 Tissue and Subcellular Distribution of MATEs

12.3 Functional Characteristics of MATE Transporters

12.4 Kinetics and Selectivity of MATE-Mediated Transport

12.5 Molecular/Structural Characteristics of MATE Transporters

12.6 Regulation of MATE and Activity

12.7 Influence of MATEs on Renal OC Clearance and Clinical Drug–Drug Interactions

12.8 Conclusions

Acknowledgments

References

13 Drug Transport in the Liver

13.1 Hepatic Physiology: Liver Structure and Function

13.2 Hepatic Uptake Transport Proteins

13.3 Hepatic Efflux Transport Proteins

13.4 Regulation of Hepatic Drug Transport Proteins

13.5 Disease State Alterations in Hepatic Transport Proteins

13.6 Model Systems for Studying Hepatobiliary Drug Transport

13.7 Drug Interactions in Hepatobiliary Transport

13.8 Interplay between Drug Metabolism and Transport

13.9 Hepatic Transport Proteins as Determinants of Drug Toxicity

13.10 The Future of Hepatic Drug Transport

Acknowledgments

References

14 Drug Transport in the Brain

14.1 Introduction

14.2 Physiology of the Brain Barriers and Brain Parenchyma

14.3 Functional Expression of Drug Transporters in the Brain

14.4 Relevance of Drug Transporters in CNS Disorders

14.5 Regulation of Drug Transporters by Nuclear Receptors in the Brain

14.6 Conclusion

References

15 Drug Transport in the Kidney

15.1 Introduction

15.2 Families of Renal Drug Transporters

15.3 Regulation of Renal Drug Transporters

15.4 Pharmacokinetic and Pharmacological/Toxicological Aspects

15.5

In Vitro

Model Systems for Studying Renal Drug Transport

15.6 FDA and EMA Draft Guidance/Guideline for Drug–Drug Interaction Studies

15.7 Perspectives

References

16 Drug Transporters in the Intestine

16.1 Introduction

16.2 Intestinal Drug Permeation

16.3 Drug Transporters in the Small Intestine

16.4 Impact of Small Intestinal Transporters on Oral Absorption of Drugs

16.5 Functional Modulation of Intestinal Transporters to Optimize Oral Absorption of Drugs

16.6 Concluding Remarks

References

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 Summary

References

18 Experimental Approaches to the Study of Drug Transporters

18.1 Introduction

18.2

In Vivo

Experiments

18.3 Isolated Tissue Methods

18.4 Primary Cell Cultures and Established Model Cell Lines

18.5 Membrane Vesicles

18.6 Analysis of Drug Interaction Mechanisms

18.7 Perspectives

References

19 Transporters in Drug Discovery:

In Silico

Approaches

19.1 Introduction

19.2 Physicochemical Determinants of Hepatobiliary Elimination

19.3

In Silico

Models for Biliary Excretion

19.4 Physicochemical Determinants of Renal Elimination

19.5

In Silico

Models of Renal Excretion

19.6 PhysiCochemical Determinants of Brain Penetration

19.7

In Silico

Approaches and SAR of Clinical Relevant Transporters

19.8 Strategies to Assess Transporter Involvement during Drug Discovery

19.9 Conclusions

References

20 Polymorphisms of Drug Transporters and Clinical Relevance

20.1 Genetic Variation and Drug Response

20.2 Genetic Variation in Membrane Transporters

20.3 Functional Analysis of Transporter Variants

20.4 Clinical Significance of Transporter Variants

References

21 Diet/Nutrient Interactions with Drug Transporters

21.1 Introduction

21.2 Diet/Nutrient Interactions with Drug Transporters

21.3 Conclusions

Acknowledgment

References

22 Clinical Relevance: Drug–Drug Interactions, Pharmacokinetics, Pharmacodynamics, and Toxicity

22.1 Introduction

22.2 Interactions Mediated by ABC Drug Transporters

22.3 Interactions Mediated by Organic Anion and Cation Transporters (Solute Carrier Family, SLC22)

22.4 Interactions Mediated by Peptide Transporters (PEPTs, SLC15)

22.5 Interactions Mediated by Multidrug and Toxin Extrusion Transporters (MATEs, SLC47)

22.6 Interactions Mediated by Monocarboxylate Transporters (MCTs, SLC16)

22.7 Interactions Mediated by Nucleoside (Concentrative and Equilibrative) Transporters (CNTs/ENTs, SLC28/29)

22.8 Conclusions

References

23 Regulatory Science Perspectives on Transporter Studies in Drug Development

23.1 Introduction

23.2 Regulatory Science Perspectives on Transporter Studies

23.3 Recent FDA NDA Review Examples

23.4 Conclusion and Future Directions

Acknowledgments

Abbreviation List

References

Index

Wiley Series in Drug Discovery and Development

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Classifications of representative drug transporters

Chapter 02

Table 2.1 Human cation and zwitterion transporters of the

SLC22

transporter family

Table 2.2 Model substrates for analysis of transport activity

Table 2.3 Substrates of hOCT1, hOCT2, and hOCT3

Table 2.4 High-affinity inhibitors of hOCT1-3

Chapter 03

Table 3.1 OAT Family Members

Chapter 04

Table 4.1 Human SLCO transporters

Table 4.2 Tissue expression of human OATPs

Table 4.3 Selected substrates, nonsubstrates, and inhibitors of human OATPs

Table 4.4 Selected

SLCO

genetic variants

Table 4.5 Drug pharmacokinetics associated with

SLCO

genotypes

Table 4.6 Selected drug interactions involving OATPs

Chapter 05

Table 5.1 A list of mammalian members of the POT family of transporters

Table 5.2 Summary of the molecular and functional characteristics of established human oligopeptide transporters and splice variants

Chapter 06

Table 6.1 Representative substrates of MCTs and SMCTs

Table 6.2 Representative inhibitors of MCTs, SMCTs, and MPCs

Chapter 07

Table 7.1 Molecular and functional characteristics of human nucleoside transporters

Table 7.2 Apparent affinities (

K

m

) of various hCNTs and hENTs for adenosine

Chapter 09

Table 9.1 Pgp substrates and modulators

Chapter 10

Table 10.1 Nomenclature and properties of the human

ABCC

genes and ABCC proteins

Table 10.2 Substrate and drug resistance profiles of human ABCC/MRP transporters (nonexhaustive list)

Table 10.3 Knockout mouse models with disrupted

Abcc

genes

Table 10.4 Major sites of ABCC protein expression in normal human tissues and ABCC protein expression in selected human tumors

Table 10.5 Genomic variations in the human

ABCC2

gene identified in patients with Dubin–Johnson syndrome affecting the ABCC2 protein sequence

Table 10.6 Genotype–phenotype correlations of ABCC1 in humans

Table 10.7 Genotype–phenotype correlations of ABCC2 in humans

Table 10.8 Genotype–phenotype correlations of ABCC4 in humans

Chapter 11

Table 11.1 Substrates and inhibitors of ABCG2

Table 11.2 Summary of investigations measuring ABCG2 expression or function in leukemia

Table 11.3 Selection of the most significant ABCG2 mutations and their impact on response to various drugs and disease risk

Chapter 12

Table 12.1 Kinetics of human MATE-mediated transport

Table 12.2 IC

50

values for ligand inhibition of MATE-mediated substrate transport

Chapter 13

Table 13.1 Uptake transporter substrates

Table 13.2 Efflux transporter substrates

Table 13.3 Nuclear receptors (NRs) and transporter regulation

Table 13.4 Model systems for studying hepatic drug transport: summary of major applications and advantages/disadvantages

Table 13.5 Examples of clinically relevant transporter-mediated DDIs

Chapter 15

Table 15.1 Drug transporters expressed in kidney

Chapter 16

Table 16.1 List of well-studied drug transporters in the intestine

Chapter 18

Table 18.1 Methods for the study of transporter

Table 18.2 Novel methods in the transporter research field

a

Chapter 19

Table 19.1 Relationship between rat biliary excretion (%) and physicochemical properties

Table 19.2 Mean (median) values of the physicochemical properties of rat and human OATP transporter substrates

Chapter 20

Table 20.1 Genetic variation in membrane transporters identified in GWAS

Table 20.2 Functional consequences of selected SLC and ABC membrane transporter variants associated with clinical outcomes

Table 20.3 Summary of validated clinical associations with SLC and ABC membrane transporter polymorphisms

Chapter 21

Table 21.1 Effects of dietary supplements on drug transporters

Table 21.2 Chemical structures of subclasses of flavonoids

Table 21.3 Interactions of flavonoids with P-gp

Table 21.4 Interactions of flavonoids with MRPs

Table 21.5 Interactions of flavonoids with BCRP

Table 21.6 Interactions of flavonoids with OATPs

Chapter 22

Table 22.1 Examples of the possible involvement of MDR1 in clinical drug–drug interactions

Table 22.2 Brain distribution of dual Pgp and BCRP substrates

Table 22.3 Examples of the possible involvement of organic anion and cation transporters in clinical drug–drug interactions

Chapter 23

Table 23.1 Selected transporter-mediated clinically significant DDIs

Table 23.2 Selected examples of NMEs approved in 2012 with transporter-related labeling information and/or postmarketing requirement/postmarketing commitment (PMR/PMC) studies

List of Illustrations

Chapter 02

Figure 2.1 Structure models of rOct1 with amino acids that are critical for substrate affinity. Modeling of the outward- and inward-facing conformation was performed using tertiary structures of LacY in the outward- and inward-facing conformations. Mutagenesis experiments showed that the indicated amino acids are critical for affinity and/or selectivity of the substrates TEA and MPP and suggest that extracellular and intracellular corticosterone interacts with F160, W218, R440, L447, and D475. (a) Predicted membrane topology of rOct1. (b) Modeled tertiary structure of rOct1 in the outward-facing conformation (side view). (c) Modeled tertiary structure of the inward-facing conformation (side view).

Figure 2.2 Location of human organic cation and zwitterion/organic cation transporters in enterocytes (a), hepatocytes (b), renal proximal tubule cells (c), airway epithelial cells (d), syncytiotrophoblast of the placenta (e), endothelial cells of the blood–barrier (f), brain neurons (g), and immune cells. Transporters of the

SLC22

family are prepresented by filled circles, whereas transporters of other families that transport organic cations are presented by open symbols. Abbreviated names of transporters that do not belong to the

SLC22

family are the following: MDR1 (

ABCB1

), MATE1 (

SLC47A1

), and MATE2-K (isoform of

SLC47A2

, NM_001099646). NC, noncharged compound; OC

+

, organic cation; ZI, zwitterion.

Chapter 03

Figure 3.1 Clustering of

OAT

genes. Screenshot taken from the Genome Browser at http://genome.ucsc.edu depicting the OAT cluster region on human chromosome 11 [109]. Panel along the top is a “macroscopic” view of human chromosome 11; the vertical bar (grey) seen on the long arm just adjacent to the centromere demarcates the location of the approximately 0.6 million-base-pair OAT cluster found on chromosome 11. Bottom panel is an expanded view of this OAT cluster. Six genes, two named OATs (

SLC22A6/OAT1, SLC22A8/OAT3

), and four putative OAT transporters (

SLC22A24, SLC22A25, SLC22A10, SLC22A9

) are found clustered within this region.

Figure 3.2 Diagrammatic representation of the proposed transmembrane topology for the organic anion transporters based on hydropathy analysis. The OATs are believed to possess 12 transmembrane domains (TMDs) with multiple glycosylation (G) and phosphorylation (P) sites on the large loops between TMDs 1 and 2 and TMDs 6 and 7, respectively.

Figure 3.3 Schematic representation of the tertiary active transport of organic anions. (A) Organic anions gain entry to the cell via the OATs found along the basolateral membrane in a process linked to the exchange and exit of dicarboxylates (DC) down their concentration gradient. (B) The Na

+

/dicarboxylate contransporter maintains the high level of intracellular dicarboxylates in a process ultimately driven by the Na

+

gradient established by the action of the Na

+

/K

+

ATPase (C). The organic anions will traverse the cytoplasm exiting the luminal aspect of the cell via transporters found in the apical membrane (E).

Figure 3.4 Modeling of OAT1 reveals a “tilting” access mechanism. (a) Computational representation of OAT1 (white) embeded within the phospholipid bilayer (gray). (b) Two superimposed OAT1 conformers derived at different times of molecular dynamic (MD) simulation (pale gray-40 ns; black-94 ns). Conformation changes in the transporter are visible. (c-Top) Conformational changes in OAT1 as determined by the distance between the C-α atoms of two amino acid residues located on different hemidomains of the transporter during 100 ns of MD simulation of substrate transport [extracellular (black) and intracellular (gray)]. (c-Bottom) Schematic representation of the conformational changes in Oat1 corresponding to time zero and after 100 ns of MD simulation (top of bars—extracellular face (black line), bottom of bars—intracellular face (gray line)). The channel in OAT1 (arrow in A) is open more after 100 ns of MD simulation.

Figure 3.5 Expression and functional profile of SLC transporters during kidney development. (a) Expression of SLC transporters during rodent kidney development (EE, early embryonic; IE, intermediate embryonic; LE, late embryonic; PN, postnatal; M, mature). (b) Oat1/Slc22a6 (black line) and Oat3/Slc22a8 (gray line) expression during rat kidney development from the onset of organogenesis (e13) to adulthood (ad). (c) Transcriptomic analyses of laser-capture microdissected portions of the developing mouse kidney (the GUDMAP consortium) [110], revealed specific upregulation of transporters in the developing proximal tubule (indicated by arrowhead). (d) Determination of elimination constant, volume of distribution, and PAH clearance for 1, 2, and 3 week postnatal mice. (N = at least 4 sets of 4 mice; means ± SEM).

Figure 3.6 HNF4α involvement in the developmental expression of Oats. (a) Interaction network of genes that differ significantly in the maturing nephron. HNF4α is the most connected gene in the network. (b) Bar graph showing ChIP-qPCR for the number of binding events for an HNF4α antibody to Oat3 (Slc22a8), Oat1 (Slc22a6), and Oct1 (Slc22a1) promoters.

Figure 3.7 Localization of organic anion uptake in embryonic kidneys. The uptake of fluorescent Oat substrates was examined in cultured mouse embryonic kidneys. (a) Uptake of fluorescent substrate (green) is evident in the developing tubular structures other than collecting ducts as revealed by staining with

Dolichos biflorus

lectin (red—a marker of collecting duct derived structures). (b) Higher power view (CD, collecting duct; CF, carboxyfluorescein). (c) Uptake of fluorescent substrate (green) is within the developing proximal tubule as revealed by staining with

Lotus

lectin (red—a marker of nascent proximal tubule). (d) Higher power view (CD, collecting duct; DT, distal tubule; PT, proximal tubule). Accumulation of the substrate can be seen.

Figure 3.8 Oat3 pharmacophores based on cationic substrates capable of interacting with the transporter. A set of 14 organic cations were assessed for their ability to interact with organic anion transporters. A four-feature pharmacophore model of the Oat3-cation interactions was created by computational analysis of the 10 molecules which interacted with Oat3. Superimposing this pharmacophore model on four of the tested compounds reveals potential Oat3-interaction sites. (Features of pharmacophore coded as follows: 1, 2—hydrogen bond acceptor, 3—hydrophobic, 4—positive ionizable.)

Chapter 05

Figure 5.1 This schematic illustrates the potential parallel/competing pathways available for oligopeptide- and peptide-based drug permeation and their potential intracellular fates across cellular barriers. Depicted are PepT1, PHT1, PHT2, and PT1 as the concentrative oligopeptide transporters. PepT2 is not expressed in intestinal epithelial cells and is therefore not illustrated here.

Figure 5.2 The effective permeability of the physiological barrier is a function of all competing transport pathways. This schematic illustrates some of the rate-limiting mass transfer resistances/characteristics of the parallel paths oligopeptide-based compounds typically encounter as they traverse cell barriers.

Figure 5.3 This schematic demonstrates the potential pathways of SQV and the peptide prodrugs of SQV permeation across the intestinal epithelium. This schematic illustrates that the rate-limiting steps to intestinal absorption of SQV include efflux (P-gp, MRP1, and MRP2) with concerted metabolism (CYP3A4 and phase II conjugation) that limit its ability to traverse the epithelial cell barrier. Upon modification with valine–valine or glycine–valine, the resulting peptide prodrugs of SQV can undergo active influx transport through an influx transporter, for example, PepT1, and minimize the effects of efflux and metabolism on absorption. The incorporation of

d

-Val-

d

-Val-SQV results in the greatest reduction in hepatic elimination and does not affect the transepithelial permeation via influx transporter(s), for example, PepT1, and basolateral efflux by unknown efflux transporter(s) into the blood/lymphatic drainage. We hypothesize that PHT1 might be a basolateral transporter capable of mediating efflux into the blood/lymphatic drainage, although that remains to be demonstrated. Figure prepared using the Motfolio™ figure package.

Chapter 06

Figure 6.1 Phylogenic relationships of SLC5 family members. The carriers in this family that are SMCTs are highlighted in the shaded box. Abbreviations for other SLC5 members and their substrates are also shown.

Figure 6.2 Putative membrane structure of SMCT1. The amino acid sequence of SMCT1 was threaded onto a previously characterized 3D structure of a membrane transporter, the

Vibrio parahaemolyticus

sodium/galactose symporter (vSGLT), based on sequence homology. Each colored ribbon represents 1 of the 13 transmembrane segments.

Chapter 07

Figure 7.1 Core chemical structures of a purine nucleoside and a pyrimidine nucleoside with numbered positions.

Figure 7.2 Predicted secondary structures of hCNT1 (a) and hENT1 (b). The N-glycosylation sites are indicated as “Y.” TMDs critical for substrate recognition are shaded in gray. Selected amino acid residues of functional importance are labeled and shown in dark circles. Reproduced with permission from Ref. 121.

Figure 7.3 Proposed membrane localization of hCNTs and hENTs in epithelial cells of the small intestine (a), kidney (b), liver (c), placenta (d), and blood–CSF barrier (e), and in endothelial cells forming the blood–brain barrier (f).

Chapter 08

Figure 8.1 Transporters involved in the enterohepatic circulation of bile salts and bile formation. Bile salts are taken up into the ileocyte from the intestinal lumen by the sodium-dependent transporter ASBT and putatively trafficked through the ileocyte by I-BABP. Bile acids are effluxed from the ileocyte to portal venous blood by the action of the OSTα/OSTβ heterodimer. At the basolateral membrane of the hepatocyte, the main bile acid uptake system is NTCP, which transports bile acids from portal blood in a sodium-dependent manner. OATP1B1 may also contribute to hepatic bile salt uptake in a sodium-independent manner. In normal conditions, very little, if any, bile salts are effluxed back to portal blood at the basolateral membrane of hepatocytes. However, in states of cholestasis, expression of the bile salt spillover pumps MRP3 and MRP4 is increased, and they may mediate efflux of bile salts into systemic circulation. The main efflux system for bile salts from hepatocytes into bile is BSEP at the canalicular hepatocyte membrane. In addition, MRP2 may also export divalent and sulfated or glucuronidated bile salts into bile. MDR3 and the ABCG5/ABCG8 heterodimer transport phospholipids and cholesterol, respectively, from hepatocytes into bile.

Figure 8.2 Bile salt-induced, FXR-dependent transcriptional mechanisms that regulate the genes encoding enterohepatic bile salt transporters. FXR activated by bile salts induces the expression of the intestinal (OSTα/OSTβ) and hepatic (BSEP, MRP2) bile salt efflux systems, as well as of the intestinal intracellular bile salt transporter (I-BABP), via direct binding to its response elements in the respective regulatory promoter regions. FXR binds DNA as a heterodimer with the nuclear receptor RXR. Decreased expression of the intestinal (ASBT) and hepatic (NTCP) bile salt uptake transporters occurs by a mechanism that indirectly involves FXR. In this cascade, bile salt-activated FXR induces the expression of the transcriptional repressor SHP, which subsequently interferes with the activity of the transactivator proteins that regulate the expression of the genes encoding bile salt uptake systems. In the case of the human

SLC10A1

(NTCP) and

SLC10A2

(ASBT) promoters, the transactivator targeted by SHP is the steroid receptor GR. In the context of the human

SLC10A2

promoter, the nuclear receptor heterodimer RAR–RXR has been suggested as an alternative or parallel target for SHP-mediated transcriptional suppression.

Chapter 09

Figure 9.1 Structures of some representative Pgp substrates and modulators.

Figure 9.2 X-ray crystal structures of mouse Pgp and other ABC transporters. (a) The inward-facing conformation of Pgp in the absence of nucleotide (PDB 3G61) [18]. (b) An ATP-sandwich dimer formed by the NBD subunit of the bacterial ABC exporter HlyB (PDB 2FGJ). The Walker A motifs (purple), Walker B motifs (orange), and signature C motifs (red) are shown, and the two bound ATP molecules are displayed space-filling format in green. (c) The outward-facing conformation of a closely related bacterial ABC protein, the lipid A flippase, MsbA (PDB 1XEF). The two homologous halves of each structure are shown in blue and gold, with domain swapping of the two TMD bundles clearly evident.

Figure 9.3 The drug-binding pocket of mouse Pgp as seen in the X-ray crystal structure. (a) Close-up view (4.4 Å resolution) of QZ59-RRR (purple, space-filling format) occupying the middle site in the drug-binding pocket, with the volumes of nearby side chains shown in gray shading. (b) Close-up view of the two QZ59-SSS molecules occupying the upper and lower sites (yellow and red, respectively, space-filling format) in the drug-binding pocket, with the volumes of nearby side chains shown in gray shading.

Figure 9.4 (a) Vacuum cleaner and flippase models of Pgp action. In the vacuum cleaner model (left side), drugs (both substrates and modulators) partition into the lipid bilayer and interact with Pgp within the membrane. They are subsequently pumped out into the aqueous phase on the extracellular side of the membrane. In the flippase model (right side), drugs partition into the membrane, interact with the drug-binding pocket in Pgp located within the cytoplasmic leaflet, and are then translocated, or flipped, to the outer membrane leaflet. Drugs will be present at a higher concentration in the outer leaflet compared to the inner leaflet, and an experimentally measurable drug concentration gradient is generated when drugs rapidly partition from the two membrane leaflets into the aqueous phase on each side of the membrane. (b) The effect of membrane partitioning on drug binding to Pgp. The binding affinity of Pgp for a substrate or modulator (

K

d

) is related to its lipid–water partition coefficient (

K

lip

). A drug with a high value of

K

lip

(left side) will accumulate to a high concentration within the membrane. This will favor binding to Pgp and result in a lower apparent

K

d

. In contrast, a drug with a low value of

K

lip

(right side) will have a lower membrane concentration and a higher apparent

K

d

.

Chapter 10

Figure 10.1 Topology of the human ABBC subfamily members. Schematic representation of the ABC core structure with two MSDs, MSD1 and MSD2, each followed by the NBDs, NBD1 and NBD2, respectively, shared by ABCC4, ABCC5, ABCC11, and ABCC12. An additional amino-terminal MSD0, which precedes the ABC core structure, is predicted for ABCC1-3, ABCC6, and ABCC10. The number of transmembrane segments in MSD2 of ABCC2 remains unclear, varying between four and six depending on the algorithms used.

Figure 10.2 Phylogenetic tree of ABCC/Abcc proteins from different vertebrate species. Cluster alignment and construction of the tree was performed using the neighbor-joining algorithm of ClustalX 2.1 [27]. Visualization of the tree as a rooted phylogram with dendroscope 3.2.3 [28].

Figure 10.3 Subcellular localization of ABCC/MRP efflux transporters. (a) Schematic representation of polarized MDCK cells recombinantly expressing human ABCC/MRP efflux transporters, which acquire a domain-specific localization, either in the apical membrane (ABCC2, ABCC11) or in the basolateral membrane (ABCC3, ABCC4, ABCC5, ABCC6). (b) Confocal laser scanning micrographs of ABCC/MRP efflux transporters in human hepatocytes. At least four different ABCC/MRP transporters have been identified in human hepatocytes, that is, ABCC2 (red) in the canalicular (apical) membrane and ABCC3, ABCC4, and ABCC6 (green) in the sinusoidal (basolateral) membrane. Bars, 20 µm. (c) Confocal laser scanning micrographs of MDCK cells simultaneously expressing recombinant human OATP2B1 (green) as an uptake transporter and ABCC2 (red) as an efflux transporter for organic anions. The lines indicate where the optical xz-sections had been taken. These double-transfected cells serve as valuable tools to study the vectorial transport of organic anions that undergo hepatobiliary elimination. In human hepatocytes, OATP2B1 (green) is located in the sinusoidal membrane and ABCC2 (red) in the canalicular membrane. Bars, 10 µm.

Chapter 11

Figure 11.1 Mechanisms of ABCG2 regulation. ABCG2 expression and localization are complex and regulated at different levels: during transcription, during ER processing, and during trafficking. Transcription factors and miR that regulate ABCG2 transcription are represented at the bottom, while mechanisms of protein degradation and cytoplasmic signaling pathways are depicted at the top.

Figure 11.2 The stem cell phenotype does not always identify cancer stem cells. NCI-H460 cells (a and b), Pgp-overexpressing SW620 Ad300 cells (c), or ABCG2-overexpressing MCF-7 FLV1000 cells (d) were incubated with 4 μM Hoechst 33342 for 30 min, washed, and then incubated in Hoechst-free medium for an additional 60 min. For (b), cells were incubated in Hoechst in the presence of 10 μM FTC to prevent ABCG2-mediated Hoechst transport. Reproduced with permission from Ref. 308.

Chapter 12

Figure 12.1 Cellular organization of MATE transporters within the context of renal and hepatic secretion of OCs. (a) RPT, showing the basolateral location of OCT2 and the apical location of MATE1 and MATE2/2-K. The critical supporting roles of NKA and Na

+

/H

+

exchange (NHE3/8) are also indicated. The immediately relevant driving forces for transepithelial OC transport are indicated, that is, the basolateral electrical potential difference (~ −60 mV) and the apical pH gradient (as defined by cellular pH of about 7.2 versus a tubular filtrate pH of about 7.4 in the early S1 segment that becomes gradually more acidic (~pH 6.8) by the S3 segment). The schematic placement of MATE1 and MATE2/2-K within the same RPT cells is for presentational convenience; it is not known if these proteins are coexpressed within the same RPT cells or if they are distributed differentially along the length of the tubule. (b) Hepatocyte, showing the basolateral location of OCT1 and the apical (canalicular) location of MATE1. Basolateral NKA contributes to the modest (−40 mV) membrane potential, and the absence of an apical NHE contributes to the lack of a transmembrane [H

+

] gradient.

Figure 12.2 Proposed secondary (a) and tertiary (b, c) structures of mammalian MATEs. (a) The secondary structure depicted is for MATE1, derived from the homology model of MATE1 that used the crystal structure of the prokaryotic MATE transporter NorM as a template [91]. The first 12 TMHs are colored in rainbow hues that correspond to those used in the MATE1 homology model shown in (b) and (c). The C-terminal sequence shown within the dashed box (a) shows the 13th TMH found in mammalian MATEs that was eliminated in the homology model (which was based on the 12-TMH structure of NorM). Residues in contrasting colors highlight potentially significant structural elements. The round symbols (with thick boundaries) indicate conserved cysteine (yellow), glutamate (dark orange), or histidine (purple) residues that were shown in site-directed studies to influence MATE1-mediated transport [62, 92] (the colors correspond to those used in the homology model shown in b and c). The square symbols indicate sites of SNPs in MATE1 that result in either loss of function (white) or significantly reduced function (gray) [69, 93]. The light green residues within the dashed polygon labeled “b” show the location (the cytoplasmic loop between TMH4 and TMH5) and length of sequence present in MATE2 that is absent in MATE2-K. MATE1 homology model shown looking down on the external face of the protein (b) or from the side (c). Highlighted are the residues, noted in (a), that were shown in site-directed studies to influence MATE1-mediated transport.

Chapter 13

Figure 13.1

In vivo

architecture of the liver (a) (Reproduced with permission from Ref. 159) and localization of transport proteins in hepatocytes (b) (Reproduced with permission from Ref. 20). Hepatocytes are polarized cells with two separate membrane domains facing blood and bile.

Chapter 14

Figure 14.1 Localization of selective ABC and SLC transporters at the BBB endothelium and at the CP epithelium. The arrows indicate the direction of substrate transport.

Figure 14.2 Localization of selective ABC and SLC transporters in astrocytes, microglia, and neurons. The arrows indicate the direction of substrate transport.

Chapter 15

Figure 15.1 Schematic diagram of the drug transport systems in the kidney. Urinary excretion of drugs is determined by the glomerular filtration, tubular secretion, and reabsorption from the urine. The dotted lines represent the renal handling of drugs. In the epithelial cells, various transporters are expressed and form directional transport; some facilitate secretion into the urine, and some facilitate reabsorption from the urine. Reabsorption also occurs along with the reabsorption of water. URAT1 and SLC2A9 mediate urate reabsorption across the proximal tubules. CL

r

, renal clearance; CL

RS

, clearance for the tubular secretion; f

B

, unbound fraction in the plasma; F

R

, fraction of reabsorption; GFR, glomerular filtration rate; OAs, organic anions; OCs; organic cations.

Chapter 16

Figure 16.1 Drug transport routes across intestinal epithelial cell monolayer. (a) passive transcellular diffusion; (b) paracellular transport; (c) transporter-mediated absorption; (d) transporter-mediated secretion; and (e) transcytosis.

Figure 16.2 Intestinal human transporters proteins for drugs and endogenous substances. Intestinal epithelia have several apical (luminal) membrane uptake transporters including two members of the OATP family, PEPT1, ileal ASBT, and MCT1. The apical ATP-dependent efflux pumps include BCRP, MRP2, and Pgp. The basolateral membrane of intestinal epithelia has several transporters including OCT1, the heteromeric organic solute transporter (OST

α

–OST

β

), and MRP3. To date, the clinically relevant drug transporters are all found on the apical membrane OATP, PEPT1, BCRP, and Pgp.

Chapter 17

Figure 17.1 A schematic illustration of cellular localization of major drug transporters in the ST of human placenta. ST, syncytiotrophoblast; CT, cytotrophoblast. Names of the transporters shown are explained in the text. Arrows indicate the direction of drug transport. OCT3, ENT1, and ENT2 may transport drugs in either direction, depending on their concentration gradient. MATE1 is an organic action/H

+

antiporter that likely mediates efflux of drugs from the placenta to the maternal circulation. The cellular localization of ENT2 needs to be confirmed.

Chapter 19

Figure 19.1 PCA of compounds with rat biliary excretion less than 10% (green squares), rat biliary excretion greater than or equal to 10% (red circles), rOatp1b2 substrates (yellow triangles), and the hOATP transporter substrates (blue circles). The analysis was carried out with six physicochemical properties (MW, cLogD

7.4

, HBA, HBD, % relative PSA, and RB). Dotted lines represent arbitrary boundary between the compounds with rat biliary excretion less than 10% and greater than or equal to 10%. Analysis suggested considerable overlap in the physicochemical properties of OATP transporter substrates and the compounds significantly excreted in the bile. Reproduced with permission from Ref. 19.

Figure 19.2 Physicochemical trends of human CLr. Relationship between

c

Log

D

7.4

and human CLr of acidic (a) and basic (b) compounds. Closed squares indicate net-reabsorbed compounds, and open squares indicate net-secreted compounds. (c) Ionization state distribution of compounds that show net reabsorption and net secretion [27]. (d) Physicochemical space of compounds involved in clinical DDIs, with significant decrease in CLr of a DDI victim when coadministered with a DDI perpetrator [35]. Evidently, about 75% of net-secreted compounds are ionized at physiological pH, and hydrophilic compounds (

c

Log

D

7.4

 < 1) with high hydrogen-bonding ability tend to participate in renal drug interactions.

Figure 19.3 Chemical structures of verapamil, prenylamine, and nicardipine and their structural components represented by M532, M132, C-CHN-BT, and other descriptors. Reproduced with permission from Ref. 64.

Figure 19.4 (a) Homology model structure of human ABCB1. Homology modeling was performed by using the reported bacterial ABC transporter Sav1866 structure template. (b) Structure of the intracellular loop between TMD10 and TMD11 calculated by molecular dynamics simulation. Reproduced with permission from Ref. 64.

Figure 19.5 Proposed primary and secondary ligand-binding sites of rat Mrp2. The primary binding site is assembled by two hydrophobic and two electropositive subpockets. The secondary binding site consists of two electropositive and two electronegative sites.

Chapter 21

Figure 21.1 Schematic interactions of flavonoids with P-gp and related MDR transporters.Flavonols, such as kaempferide, quercetin, and galangin, display bifunctional interactions with NBDs, at both the ATP-binding site and the hydrophobic steroid-binding region. Prenylation of flavonoids would greatly increase the hydrophobicity of flavonoids, shifting the flavonol binding outside the ATP-binding site to vicinal steroid-binding region and TMD drug-binding site.

Chapter 23

Figure 23.1 Evaluation of investigational drugs (NME) as substrates for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2K transporters. (Adapted by permission from Macmillan Publishers Ltd: Clin Pharmacol Ther [27], copyright (2013) http://www.nature.com/clpt/index.html).

a

Biliary secretion can be estimated from

in vitro

hepatocyte uptake data, sandwich-cultured hepatocyte biliary clearance or radiolabeled ADME data, and nonrenal clearance data.

b

% Active renal secretion was estimated from (CL

r

–fu*GFR)/CL

total

.

c

Modified from the current FDA draft guidance (Ref. [7]) to include MATE1/MATE2-K. dSee Ref. 7.

Figure 23.2 P-gp/BCRP inhibition tree. Decision tree to determine whether an investigational drug is an inhibitor of P-gp and when an

in vivo

clinical study is needed is shown here. A similar model can be applied to a BCRP inhibitor. (Modified from the figure in Ref. 7). [

I

]

1

represents the mean steady-state total (free and bound)

C

max

following administration of the highest proposed clinical dose. [

I

]

2

 = dose of inhibitor (in mol)/250 ml (if IC

50

is in a molar unit). For IC

50

determination, a unidirectional assay (e.g., B to A) based on the probe substrate can also be considered.

Figure 23.3 OATP inhibition tree. Decision tree to determine whether an investigational drug is an inhibitor of OATP1B1 or OATP1B3 and when an

in vivo

clinical study is needed (Modified from Figure in Ref. [7]).

a

R

-value = 1 + (fu × 

I

in,max

/IC

50

), where

I

in,max

is the estimated maximum inhibitor concentration at the inlet to the liver and is equal to

C

max

 + (

k

a

 × dose × 

F

a

F

g

/Qh).

C

max

is the maximum systemic plasma concentration of inhibitor; dose is the inhibitor dose;

F

a

F

g

is the fraction of the dose of inhibitor that is absorbed;

k

a

is the absorption rate constant of the inhibitor; and Qh is the estimated hepatic blood flow (e.g., 1500 ml/min). If

F

a

F

g

values and

k

a

values are unknown, use 1 and 0.1 min

−1

[51] for

F

a

F

g

and

k

a

, respectively because the use of theoretically maximum value can avoid false-negative prediction. For drugs whose fu values are less than 0.01 or fu cannot be accurately determined due to high protein binding, then assume fu = 0.01 to err on the conservative side to avoid false-negative predictions.

b

These are the suggested values according to the upper limit of equivalence range.

Figure 23.4 OAT1/3, OCT2, and MATE1/MATE2K inhibition tree. Decision tree to determine whether an investigational drug is an inhibitor of OAT1, OAT3, OCT2, MATE1, and MATE2K and when an

in vivo

clinical study is needed (MATE1/2K in Ref. 21 added to the figure in Refs. 1, 7; Adapted by permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (Ref. [21]), copyright (2013) http://www.nature.com/clpt/index.html and Nat Rev Drug Discov [1], copyright (2010) http://www.nature.com/nrd/index.html).

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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

Drug Transporters

Molecular Characterization and Role in Drug Disposition

Second Edition

Edited by

Guofeng You

Rutgers, the State University of New JerseyPiscataway, NJ, USA

Marilyn E. Morris

University at Buffalo, State University of New YorkBuffalo, NY, USA

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permissions.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at [phone], outside the United States at [phone] or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:Drug transporters (2007) Drug transporters : molecular characterization and role in drug disposition / edited by Guofeng You, Marilyn E. Morris. – Second edition.  p. ; cm. Includes index. ISBN 978-1-118-48993-2 (cloth) I. You, Guofeng, editor. II. Morris, Marilyn Emily, editor. III. Title. [DNLM: 1. Biological Transport–physiology. 2. Membrane Transport Proteins–physiology. 3. Pharmacokinetics. QU 120] R857.B52 571.6′4–dc 3

2014008367

This book is dedicated to our students, postdocs, and colleagueswho have challenged and inspired us in our careers, andto our families William, Sarah, Jacqueline andKathleen Morris and Yifan and Peter Zhou who remaina continuing source of love and support in our lives.

Preface to the Second Edition

Since the first edition of Drug Transporters was published 5 years ago, we have witnessed significant advances in the field: new members of transporters have been identified, new regulatory pathways have been discovered, and sophisticated techniques for validating transport process have been developed, all of which lead to a better understanding of the physiological roles and clinical implications of these transporters. As a result, a new edition to reflect these advances is both timely and necessary.

The new (second) edition will retain the same basic format as that of the first edition: the first half of the book provides an overview of the relevant drug transporters useful for both beginning and experienced scientists and researchers. The second half of the book presents the principles of drug transport and associated techniques, in sufficient detail to enable nonspecialist readers to understand them. Such readers include graduate students in the pharmacological or physiological sciences and academic or industrial scientists in related fields of study. There are 23 chapters in this edition as compared with 24 chapters in the first edition. This represents an update of most of the chapters, significant expansion of others, removal of chapters—the contents of which are incorporated into other chapters—and addition of new chapters. As a result, the new edition not only reflects where the field is today but where it will be for the foreseeable future. Like its predecessor, the new edition continues to be used as a textbook in graduate courses in drug/membrane transport and as a desk reference for researchers working in the transporter field, as well as in the areas of drug metabolism and pharmacokinetics in the pharmaceutical industry.

We would like to express our deepest gratitude and respect to our colleagues who contributed chapters in their area of expertise. We are indebted to you all. We acknowledge Jonathan Rose, who brought extraordinary dedication to his role as publishing editor, and the many professionals at Wiley who worked with us to ensure the best book possible. On a personal note, we thank our families for their love and support.

Guofeng YouMarilyn E. Morris

Preface to the First Edition

Transporters are membrane proteins that span cellular membranes and are the gatekeepers for all cells and organelles, controlling the intake and efflux of crucial endogenous substrates such as sugars, amino acids, nucleotides, and inorganic ions.

The specificity of many transporters is not, however, limited to their physiological substrates, and for some, their physiological substrates remain undiscovered. Xenobiotics (i.e., drugs, dietary, and environmental compounds) have the potential to be recognized by transporters that crucially influence the absorption, distribution, and elimination of drugs in the body.

Due to their hydrophobic nature and relatively low abundance, the molecular identification of transporters had been a difficult task until the development of the expression cloning technique for transporters in the early 1990s. This powerful approach, combined with recent genome analysis, has facilitated the identification and characterization of numerous transporters that are important in drug disposition.

Given the considerable advances in the identification of these transporters, a textbook covering basic transport mechanisms to specific descriptions of transporter families, including substrate and inhibitor specificity, subcellular and tissue localization, mechanisms governing transport, species differences, the clinical implications of these transporters in human physiology and disease, and their role in drug distribution, elimination, and interactions in drug therapy, is both timely and necessary. Such a book has not been available, so our aim is twofold: the first half of the book provides an overview of the relevant drug transporters useful for both beginning and experienced scientists and researchers. The second half of the book presents the principles of drug transport and its associated techniques in sufficient detail to enable nonspecialist readers to understand them. Such readers include graduate students in the pharmacological or physiological sciences and academic or industrial scientists in related fields of study. It is anticipated that this book will be used as a textbook in graduate courses in drug/membrane transport and as a desk reference for researchers working in the transporter field as well as in the areas of drug metabolism and pharmacokinetics in the pharmaceutical industry.

Credit for this comprehensive textbook belongs to the many dedicated scholars who contributed chapters in their area of expertise. To all we express our deepest gratitude and respect. We also acknowledge the contributions of Jonathan Rose and the many professionals at John Wiley who worked with us to ensure the best book possible. Finally, we extend our heartfelt thanks to our families for their constant support and encouragement.

Guofeng YouMarilyn E. Morris

List of Contributors

Naohiko Anzai, Department of Pharmacology, Dokkyo Medical College, Tochigi, Japan

Tamima Ashraf, Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Julian C. Bahr, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Agnes Basseville, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Susan E. Bates, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Reina Bendayan, Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Rajinder K. Bhardwaj, Clinical Pharmacokinetics, Theravance, Inc., South San Francisco, CA, USA

Vibha Bhatnagar, Departments of Medicine, and Family and Preventative Medicine, University of California, San Diego, La Jolla, CA, USA

Kim L. R. Brouwer, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Kevin T. Bush, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA

Stephen M. Carl, Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, IN; Formulation Development, Enteris BioPharma, Inc., Boonton, NJ, USA

Aparna Chhibber, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

Adam T. Clay, Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada

Lester R. Drewes, Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN, USA

Ayman El-Kattan, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research & Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA

Jyrki J. Eloranta, Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland

Hitoshi Endou, Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan

Satish A. Eraly, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

Brian C. Ferslew, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Vadivel Ganapathy, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA, USA

Olafur Gudmundsson, Bristol-Myers Squibb Research Institute, Discovery Pharmaceutics, Princeton, NJ, USA

Dea Herrera-Ruiz, Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico

Shiew-Mei Huang, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

Horace T. B. Ho, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA

Gregory Kaler, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

Yukio Kato, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Kanazawa, Japan

Richard B. Kim, Departments of Medicine, Physiology & Pharmacology and Oncology, The University of Western Ontario, London, Ontario, Canada

Gregory T. Knipp, Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, IN, USA

Kathleen Köck, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Hermann Koepsell, Department of Molecular Plant Physiology and Biophysics of the Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Germany

Deanna L. Kroetz, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA

Yoshiyuki Kubo, Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

Gerd A. Kullak-Ublick, Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland

Hiroyuki Kusuhara, Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Yurong Lai, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA

Thomas Lang, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart; University of Tübingen, Tübingen, Germany

Sue-Chih Lee, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

Zejian Liu, Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN, USA

Qingcheng Mao, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA

Janine Micheli, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, 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

Megha Nagle, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

Anne T. Nies, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart; University of Tübingen, Tübingen, Germany

Sanjay K. Nigam, Departments of Pediatrics, Medicine, Cellular and Molecular Medicine, and Bioengineering, University of California, San Diego, La Jolla, CA, USA

Robert W. Robey, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

Patrick T. Ronaldson, Department of Medical Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA

Takashi Sekine, Department of Pediatrics, Toho University School of Medicine, Tokyo, Japan

Patrick J. Sinko, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

Frances J. Sharom, Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada

Bruno Stieger, Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland

Rommel G. Tirona, Departments of Physiology & Pharmacology and Medicine, The University of Western Ontario, London, Ontario, Canada

David M. Truong, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

Akira Tsuji, Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma, Kanazawa, Japan

Jashvant D. Unadkat, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA

Manthena V. Varma, Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research & Development, Groton Laboratories, Pfizer Inc., Groton, CT, USA

Serena Marchetti, Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands

Jan H. M. Schellens, Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam; Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, the Netherlands

Joanne Wang, Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, USA

Xiaodong Wang, Department of Clinical Pharmacology, Genetech, South San Francisco, CA, USA

Stephen H. Wright, Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, USA

Wei Wu, Department of Medicine, University of California, San Diego, La Jolla, CA, USA

Guofeng You, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

Lei Zhang, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

1Overview of Drug Transporter Families

Guofeng You1 and Marilyn E. Morris2

1 Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA

2 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA

1.1 What Are Drug Transporters?

Transporters are membrane proteins whose primary function is to facilitate the flux of molecules into and out of cells. Drug transporters did not evolve to transport specific drugs. Instead, their primary functions are to transport nutrients or endogenous substrates, such as sugars, amino acids, nucleotides, and vitamins, or to protect the body from dietary and environmental toxins. However, the specificity of these transporters is not strictly restricted to their physiological substrates. Drugs that bear significant structural similarity to the physiological substrates have the potential to be recognized and transported by these transporters. As a consequence, these transporters also play significant roles in determining the bioavailability, therapeutic efficacy, and pharmacokinetics of a variety of drugs. Nevertheless, because drugs may compete with the physiological substrates of these transporters, they are also likely to interfere with the transport of endogenous substrates and consequently produce deleterious effects on body homeostasis.

1.2 Structure and Model of Drug Transporters