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Drug Transporters: Molecular Characterization and Role in Drug Disposition 2nd edition [Kietas viršelis]

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Edited by (Rutgers University), Edited by (University at Buffalo, SUNY), Series edited by (Georgia State University, Atlanta)
  • Formatas: Hardback, 528 pages, aukštis x plotis x storis: 285x226x33 mm, weight: 1470 g
  • Serija: Wiley Series in Drug Discovery and Development
  • Išleidimo metai: 21-Oct-2014
  • Leidėjas: John Wiley & Sons Inc
  • ISBN-10: 1118489934
  • ISBN-13: 9781118489932
Kitos knygos pagal šią temą:
Drug Transporters: Molecular Characterization and Role in Drug Disposition 2nd editionDidesnis paveikslėlis
  • Formatas: Hardback, 528 pages, aukštis x plotis x storis: 285x226x33 mm, weight: 1470 g
  • Serija: Wiley Series in Drug Discovery and Development
  • Išleidimo metai: 21-Oct-2014
  • Leidėjas: John Wiley & Sons Inc
  • ISBN-10: 1118489934
  • ISBN-13: 9781118489932
Kitos knygos pagal šią temą:
Pastovi nuoroda: https://www.kriso.lt/db/9781118489932.html
Raktažodžiai:
This is the second edition of a textbook for scientists and professionals dealing with chemicals used to transport drugs in the human body. It is intended for pharmacology and physiology graduate courses in drug/membrane transport and as a desk reference for researchers in the transport field and the pharmaceutical industry. The book has been revised and updated to reflect significant advances in the field: new members, new regulatory pathways, and better techniques for validating transport processes have been developed since the first edition, and the new edition reflects the resulting improvements in knowledge. The first half of the book provides an overview of relevant drug transporters for research and industry. The second half of the book presents the principles of drug transport and associated techniques, along with interactions with drugs and nutrients, toxicities, and other issues of clinical relevance. Annotation ©2014 Ringgold, Inc., Portland, OR (protoview.com)

Preface to the Second Edition xvii
Preface to the First Edition xix
List of Contributors
xxi
1 Overview of Drug Transporter Families
1(6)
Guofeng You
Marilyn E. Morris
1.1 What Are Drug Transporters?
1(1)
1.2 Structure and Model of Drug Transporters
1(1)
1.3 Transport Mechanisms
2(1)
1.4 Polarized Expression of Drug Transporters in Barrier Epithelium
2(1)
1.5 Classifications of Drug Transporters
2(2)
1.5.1 Definition of Efflux and Influx Transporters
2(1)
1.5.2 Definition of Absorptive and Secretory Transporters
2(1)
1.5.3 Relationship between Influx/Efflux and Absorptive/Secretory Transporters
2(2)
1.5.4 ABC Transporters and SLC Transporters
4(1)
1.6 Regulation of Drug Transporters
4(3)
References
4(3)
2 Organic Cation and Zwitterion Transporters (OCTs, OCTNs)
7(18)
Hermann Koepsell
2.1 Introduction
7(1)
2.2 Hoct1 (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)
7(10)
2.2.1 Basic Functional Properties of OCT1--3
8(1)
2.2.2 Structure and Proposed Transport Mechanism of OCT1--3
9(2)
2.2.3 Comparison of Substrate and Inhibitor Selectivities of hOCT1--3
11(1)
2.2.4 Distribution of hOCT1
11(1)
2.2.5 Regulation of hOCTl
11(3)
2.2.6 Physiological and Biomedical Roles of hOCT1
14(1)
2.2.7 Pathological Implications of hOCT1 and Therapeutical Aspects
15(1)
2.2.8 Distribution of hOCT2
15(1)
2.2.9 Regulation of hOCT2
15(1)
2.2.10 Physiological and Biomedical Roles of hOCT2
15(1)
2.2.11 Pathological Implications of hOCT2 and Therapeutical Aspects
16(1)
2.2.12 Distribution of hOCT3
16(1)
2.2.13 Regulation of hOCT3
16(1)
2.2.14 Physiological and Biomedical Roles of hOCT3
16(1)
2.2.15 Pathological Implications of hOCT3 and Therapeutical Aspects
17(1)
2.3 hOCTN1 (SLC22A4) and hOCTN2 (SLC22A5)
17(3)
2.3.1 Functional Properties of hOCTN1
17(1)
2.3.2 Substrates and Inhibitors of hOCTN1
17(1)
2.3.3 Distribution of hOCTN1
18(1)
2.3.4 Regulation of hOCTN1
18(1)
2.3.5 Physiological and Biomedical Roles of hOCTN1
18(1)
2.3.6 Pathological Implications of hOCTN1 and Therapeutical Aspects
18(1)
2.3.7 Functional Properties of hOCTN2
19(1)
2.3.8 Substrates and Inhibitors of hOCTN2
19(1)
2.3.9 Distribution a of hOCTN2
19(1)
2.3.10 Regulation of hOCTN2
19(1)
2.3.11 Physiological Roles and Biomedical Roles of hOCTN2
19(1)
2.3.12 Pathological Implications of hOCTN2 and Therapeutical Aspects
19(1)
2.4 hOCT6 (SLC22A16)
20(1)
2.5 Conclusions
20(5)
References
21(4)
3 Organic Anion Transporters
25(18)
Kevin T. Bush
Megha Nagle
David M. Truong
Vibha Bhatnagar
Gregory Kaler
Satish A. Eraly
Wei Wu
Sanjay K. Nigam
3.1 OAT Family
25(2)
3.1.1 Introduction
25(2)
3.1.2 Discovery
27(1)
3.1.3 Nomenclature
27(1)
3.2 Molecular Characterization
27(2)
3.2.1 Genomics
27(1)
3.2.2 Protein Structure
28(1)
3.2.3 Mechanism of Substrate Translocation
28(1)
3.3 Expression and Regulation of OATs
29(3)
3.3.1 Tissue Distribution
29(1)
3.3.2 Ontogeny
29(1)
3.3.3 Transcriptional Regulation
30(2)
3.3.4 Posttranslational Regulation
32(1)
3.4 OAT Substrates
32(3)
3.4.1 Substrates
32(1)
3.4.2 Substrate Specificity
33(1)
3.4.3 Inhibitors
34(1)
3.5 Systems Biology of OATs
35(2)
3.5.1 Physiological Role
35(1)
3.5.2 Pathophysiological Role
35(1)
3.5.3 Clinical Pharmacology
35(1)
3.5.4 Remote Communication, Sensing and Signaling
36(1)
3.6 Conclusions
37(6)
Acknowledgments
37(1)
References
37(6)
4 Organic Anion-Transporting Polypeptides
43(24)
Rommel G. Tirona
Richard B. Kim
4.1 Introduction to the OATP Superfamily
43(1)
4.1.1 Introduction
43(1)
4.1.2 Nomenclature
43(1)
4.2 Molecular Characteristics of OATPs
44(1)
4.2.1 Gene Structure
44(1)
4.2.2 Protein Structure
44(1)
4.2.3 Transport Mechanisms
45(1)
4.3 Expression and Regulation of OATPs
45(3)
4.3.1 Tissue Distribution
45(2)
4.3.2 Posttranslational Regulation
47(1)
4.3.3 Adapter Protein Interactions
47(1)
4.3.4 Transcriptional Regulation
47(1)
4.4 OATP Substrates and Inhibitors
48(5)
4.4.1 Substrates
48(5)
4.4.2 Substrate Specificity of Human OATPs
53(1)
4.4.3 Inhibitors
53(1)
4.5 Pharmacology of OATPs
53(4)
4.5.1 Pharmacogenetics
53(3)
4.5.2 Drug Interactions
56(1)
4.6 Physiological/Pathophysiological Roles
57(1)
4.6.1 Bilirubin Homeostasis
57(1)
4.6.2 Thyroid Hormone Homeostasis
57(1)
4.6.3 Bile Acid Homeostasis
57(1)
4.6.4 Steroid Hormone Homeostasis
58(1)
4.6.5 Prostaglandin Homeostasis
58(1)
4.6.6 Cancer
58(1)
4.6.7 Other Associations with Disease
58(1)
4.7 Conclusions
58(9)
Acknowledgments
58(1)
References
59(8)
5 Peptide Transporters
67(24)
Stephen M. Carl
Dea Herrera-Ruiz
Rajinder K. Bhardwaj
Olafur Gudmundsson
Gregory T. Knipp
5.1 Introduction
67(2)
5.2 Molecular and Structural Characteristics
69(4)
5.3 Functional Properties
73(1)
5.3.1 Mechanism of Transport
73(1)
5.3.2 Molecular Requirements for Substrate Recognition and Transport
73(1)
5.3.3 General Substrate Specificities
73(1)
5.3.4 Established Endogenous and Exogenous Substrates
74(1)
5.4 Regulation
74(6)
5.4.1 Dietary Regulation
74(1)
5.4.2 Developmental Regulation
75(1)
5.4.3 Regulation by Circadian Rhythms
76(1)
5.4.4 Disease State--Dependent Regulation
76(1)
5.4.5 Hormonal Regulation
77(1)
5.4.6 Regulation by Pharmaceutical Agents
78(1)
5.4.7 Single Nucleotide Polymorphisms
78(1)
5.4.8 Splice Variants
79(1)
5.5 Pharmaceutical Drug Screening
80(3)
5.5.1 Case Study: Targeting Peptide Transporters for Increased Oral Absorption
81(2)
5.6 Concluding Remarks
83(8)
Acknowledgments
84(1)
References
84(7)
6 Monocarboxylic Acid Transporters
91(16)
Zejian Liu
Lester R. Drewes
6.1 Introduction
91(1)
6.2 Mitochondrial Pyruvate Transporter Family
91(1)
6.3 SLC5 Transporter Family
92(1)
6.3.1 Structure
92(1)
6.3.2 Location and Function
92(1)
6.3.3 Pharmaceutical Substrates and Disease
93(1)
6.4 SLC16 Transporter Family
93(14)
6.4.1 Introduction
93(1)
6.4.2 Functional Roles of MCTs under Physiological Conditions and in Drug Transport
94(2)
6.4.3 Regulation of MCTs Activity
96(3)
References
99(8)
7 The Nucleoside Transporters CNTs and ENTs
107(20)
Horace T. B. Ho
Joanne Wang
7.1 Introduction
107(1)
7.2 Molecular and Functional Characteristics of CNTs (SLC28)
107(5)
7.2.1 Family Members and Substrate Specificity
107(3)
7.2.2 Transport Mode of CNTs
110(1)
7.2.3 Tissue Distribution and Cellular Localization of CNTs
110(1)
7.2.4 Interaction with Nucleoside Analogs
110(1)
7.2.5 Structure-Function Relationship of CNTs
111(1)
7.3 Molecular and Functional Characteristics of ENTs (SLC29)
112(4)
7.3.1 Family Members and Substrate Specificity
112(1)
7.3.2 Transport Mode of ENTs
113(1)
7.3.3 Tissue Distribution and Cellular Localization of ENTs
113(2)
7.3.4 Interaction with Nucleoside Analogs
115(1)
7.3.5 Structure--Function Relationship of ENTs
115(1)
7.4 Regulation of CNT and ENT Nucleoside Transporters
116(1)
7.5 Physiological and Pathophysiological Functions of CNTs AND ENTs
117(2)
7.5.1 Nucleoside Homeostasis
117(1)
7.5.2 Adenosine Signaling
118(1)
7.5.3 ENT3 in Autosomal Recessive Disorders
118(1)
7.5.4 Physiological Function of PMAT/ENT4
118(1)
7.6 Therapeutic Significance of CNTs and ENTs
119(1)
7.6.1 CNTs and ENTs in Intracellular Disposition of Nucleoside Drugs
119(1)
7.6.2 CNTs and ENTs in Pharmacokinetics of Nucleoside Drugs
120(1)
7.6.3 CNTs and ENTs as Drug Targets
120(1)
7.7 Conclusions and Future Directions
120(7)
Acknowledgment
121(1)
Abbreviations
121(1)
References
121(6)
8 Bile Salt Transporters
127(14)
Jyrki J. Eloranta
Bruno Stieger
Gerd A. Kullak-Ublick
8.1 Overview of the Enterohepatic Circulation of Bile Salts
127(1)
8.2 The Chief Transporters in the Enterohepatic Circulation of Bile Salts
127(2)
8.3 Enterohepatic Bile Salt Transporters in Liver Disease
129(1)
8.4 Control of Bile Salt Transport and Metabolism
130(1)
8.5 Nuclear Receptors as Transcriptional Regulators of Bile Salt Homeostasis
130(2)
8.5.1 FXR: The Master Regulator of Bile Salt Transport and Homeostasis
131(1)
8.5.2 The Role of PXR and VDR as Bile Salt Sensors
132(1)
8.5.3 The Bile Salt-Induced Transcriptional Repressor SHP
132(1)
8.6 FXR-Dependent Mechanisms That Regulate Human Bile Salt Transporter Genes
132(3)
8.6.1 Positive Feedforward Control of Bile Salt Efflux Systems by Bile Salts
132(2)
8.6.2 Negative Feedback Control of Bile Salt Uptake Systems by Bile Salts
134(1)
8.6.3 Impact of Genetic Variants of FXR on Bile Salt Homeostasis
134(1)
8.7 Cross Talk between the Transcriptional Control of Bile Salt and Drug Transporters
135(1)
8.8 Concluding Remarks and Future Perspectives
135(6)
References
135(6)
9 Multidrug Resistance Protein: P-Glycoprotein
141(20)
Adam T. Clay
Frances J. Sharom
9.1 The P-Glycoprotein Gene Family
141(1)
9.2 Tissue Distribution of P-Glycoprotein
141(1)
9.3 Role of P-Glycoprotein in Human Physiology
141(2)
9.4 P-Glycoprotein Substrates and Modulators
143(1)
9.5 P-Glycoprotein Structure
143(3)
9.6 Subcellular Systems for Studying P-Glycoprotein
146(1)
9.7 ATP Binding and Hydrolysis by P-Glycoprotein
147(1)
9.8 Drug Binding by P-Glycoprotein
148(1)
9.9 P-Glycoprotein-Mediated Drug Transport
148(1)
9.10 Substrate Specificity of P-Glycoprotein and the Nature of the Drug-Binding Site
149(1)
9.11 P-Glycoprotein as a Hydrophobic Vacuum Cleaner or Drug Flippase
150(1)
9.12 Role of the Lipid Bilayer in P-Glycoprotein Function
151(2)
9.13 Mechanism of Action of P-Glycoprotein
153(1)
9.14 Role of P-Glycoprotein in Drug Therapy
154(1)
9.15 Modulation of P-Glycoprotein in Cancer Treatment
154(1)
9.16 Regulation of P-Glycoprotein Expression
155(1)
9.17 P-Glycoprotein Gene Polymorphisms and Their Implications in Drug Therapy and Disease
155(1)
9.18 Summary and Conclusions
156(5)
References
157(4)
10 Multidrug Resistance Proteins of the ABCC Subfamily
161(26)
Anne T. Nies
Thomas Lang
10.1 Introduction
161(1)
10.2 Molecular Characteristics
162(1)
10.3 Functional Properties, Substrate Specificity, and Multidrug Resistance Profiles of Human ABCC/MRPs
163(4)
10.4 Localization of ABCC/MRP Efflux Transporters in Normal Human Tissues and in Human Cancers
167(4)
10.4.1 ABCC1
170(1)
10.4.2 ABCC2
170(1)
10.4.3 ABCC3
170(1)
10.4.4 ABCC4
170(1)
10.4.5 ABCC5
171(1)
10.4.6 ABCC6
171(1)
10.4.7 ABCC10, ABCC11, and ABCC12
171(1)
10.5 Genotype--Phenotype Correlations and Clinical Consequences of Genetic Variants in ABCC Genes
171(7)
10.5.1 Genetic Variants of Human ABCC/MRP Genes and the Mendelian Inheritance of Diseases and Syndromes
172(1)
10.5.2 Genetic Variants of Human ABCC/MRP Genes and Clinical Consequences
On Drug Response and Susceptibility to Complex Disease
173(5)
10.6 Conclusions and Future Prospects
178(9)
Acknowledgments
179(1)
References
179(8)
11 Breast Cancer Resistance Protein (BCRP) or ABCG2
187(36)
Agnes Basseville
Robert W. Robey
Julian C. Bahr
Susan E. Bates
11.1 Discovery and Nomenclature
187(1)
11.2 ABCG2 Gene and Expression
187(4)
11.2.1 The ABCG2 Gene
187(1)
11.2.2 Factors Controlling ABCG2 Expression
188(3)
11.3 Physical Properties
191(3)
11.3.1 Structure
191(2)
11.3.2 Trafficking and Regulation of Cell Surface Expression
193(1)
11.4 Substrates/Inhibitors of ABCG2
194(1)
11.4.1 Endogenous Substrates
194(1)
11.4.2 Exogenous Substrates
194(1)
11.4.3 Inhibitors
195(1)
11.5 Recent Findings in Physiological Function
195(4)
11.5.1 ABCG2, Urate, and Gout
195(4)
11.5.2 Jr(a--) Phenotype
199(1)
11.6 Predicted Physiological Function from Tissue Distribution
199(3)
11.6.1 Stem Cells
200(1)
11.6.2 Placenta
201(1)
11.6.3 Mammary Gland
201(1)
11.6.4 Testis
201(1)
11.6.5 Blood--Brain Barrier
201(1)
11.6.6 Liver and the Gastrointestinal Tract
202(1)
11.6.7 Kidneys
202(1)
11.7 ABCG2 Expression in Cancer and Its Role in Drug Resistance
202(3)
11.8 Genetic Polymorphisms
205(3)
11.8.1 Inventory
205(1)
11.8.2 Q141K and Drug Disposition/Clinical Outcome
206(1)
11.8.3 Other Polymorphisms and Drug Disposition/Clinical Outcome
206(2)
11.9 Conclusion
208(15)
References
208(15)
12 Multidrug and Toxin Extrusion Proteins
223(22)
Stephen H. Wright
12.1 Introduction
223(2)
12.1.1 MATE Activity in the Context of the Cellular Physiology of Renal and Hepatic Organic Cation Secretion
223(1)
12.1.2 The Cellular Basis of Renal OC Secretion
224(1)
12.2 Tissue and Subcellular Distribution of MATEs
225(1)
12.3 Functional Characteristics of MATE Transporters
226(1)
12.4 Kinetics and Selectivity of MATE-Mediated Transport
227(6)
12.4.1 Kinetics
227(2)
12.4.2 Selectivity
229(4)
12.5 Molecular/Structural Characteristics of MATE Transporters
233(3)
12.6 Regulation of MATE and Activity
236(1)
12.7 Influence of MATEs on Renal OC Clearance and Clinical Drug--Drug Interactions
237(1)
12.8 Conclusions
238(7)
Acknowledgments
238(1)
References
238(7)
13 Drug Transport in the Liver
245(28)
Brian C. Ferslew
Kathleen Kock
Kim L. R. Brouwer
13.1 Hepatic Physiology: Liver Structure and Function
245(1)
13.2 Hepatic Uptake Transport Proteins
245(2)
13.3 Hepatic Efflux Transport Proteins
247(2)
13.3.1 Canalicular Transport Proteins
248(1)
13.3.2 Basolateral Efflux Transport Proteins
249(1)
13.4 Regulation of Hepatic Drug Transport Proteins
249(4)
13.4.1 Transcriptional Regulation
249(1)
13.4.2 Posttranslational Regulation
250(3)
13.5 Disease State Alterations in Hepatic Transport Proteins
253(2)
13.5.1 Cholestasis
253(1)
13.5.2 Dubin--Johnson Syndrome
253(1)
13.5.3 Rotor Syndrome
254(1)
13.5.4 Nonalcoholic Steatohepatitis
254(1)
13.5.5 Inflammation and Inflammation-Induced Cholestasis
254(1)
13.5.6 Human Immunodeficiency Virus (HIV) Infection
255(1)
13.5.7 Chronic Hepatitis C Virus (HCV) Infection
255(1)
13.6 Model Systems for Studying Hepatobiliary Drug Transport
255(5)
13.6.1 In Vitro Systems
255(4)
13.6.2 In Vivo Systems
259(1)
13.7 Drug Interactions in Hepatobiliary Transport
260(2)
13.8 Interplay between Drug Metabolism and Transport
262(1)
13.9 Hepatic Transport Proteins as Determinants of Drug Toxicity
263(1)
13.10 The Future of Hepatic Drug Transport
263(10)
Acknowledgments
264(1)
References
264(9)
14 Drug Transport in the Brain
273(30)
Tamima Ashraf
Patrick T. Ronaldson
Reina Bendayan
14.1 Introduction
273(1)
14.2 Physiology of the Brain Barriers and Brain Parenchyma
273(1)
14.2.1 Blood--Brain Barrier
273(1)
14.2.2 Cellular Compartments of the Neurovascular Unit and Brain Parenchyma
274(1)
14.2.3 Blood--Cerebrospinal Fluid Barrier
274(1)
14.3 Functional Expression of Drug Transporters in the Brain
274(9)
14.3.1 ATP-Binding Cassette Drug Efflux Transporters
274(4)
14.3.2 Solute Carrier (SLC) Drug Transporters
278(5)
14.4 Relevance of Drug Transporters in CNS Disorders
283(6)
14.4.1 Brain Tumors
283(1)
14.4.2 Brain HIV-1 Infection
284(1)
14.4.3 Epilepsy
284(1)
14.4.4 Neurodegenerative Diseases
285(1)
14.4.5 Cerebral Hypoxia and Ischemic Stroke
286(1)
14.4.6 Pain
287(2)
14.5 Regulation of Drug Transporters by Nuclear Receptors in the Brain
289(1)
14.6 Conclusion
290(13)
References
291(12)
15 Drug Transport in the Kidney
303(24)
Hiroyuki Kusuhara
Takashi Sekine
Naohiko Anzai
Hitoshi Endou
15.1 Introduction
303(2)
15.2 Families of Renal Drug Transporters
305(5)
15.2.1 Organic Anion Transporter Family (OAT Family Encoded by SLC22)
305(2)
15.2.2 Organic Anion-Transporting Polypeptide (OATP) Family (SLCO)
307(1)
15.2.3 Organic Cation Transporter (OCT) Family (SLC22)
308(1)
15.2.4 OCTN/Carnitine Transporter Family
308(1)
15.2.5 Multidrug and Toxin Extrusion Family (SLC47)
309(1)
15.2.6 Peptide Transporter (PEPT) Family (SLC15)
309(1)
15.2.7 Sodium/Phosphate Transporter Type 1 (NPT1) Family (SLC17)
309(1)
15.2.8 Na+-Coupled Concentrative Nucleoside Transporter (CNT/SLC28) and Equilibrative Nucleoside Transporter (ENT/SLC29)
309(1)
15.2.9 MDR1/P-Glycoprotein(ABCB1)
310(1)
15.2.10 Multidrug Resistance-Associated Protein (MRP) Family (ABCC)
310(1)
15.2.11 Breast Cancer Resistance Protein (BCRP) (ABCG2)
310(1)
15.3 Regulation of Renal Drug Transporters
310(2)
15.3.1 Phosphorylation
310(1)
15.3.2 Glycosylation
311(1)
15.3.3 Protein--Protein Interaction
311(1)
15.3.4 Gender and Developmental Differences
311(1)
15.3.5 Epigenetic Regulation
311(1)
15.4 Pharmacokinetic and Pharmacological/Toxicological Aspects
312(3)
15.4.1 Pharmacokinetic Aspects
312(2)
15.4.2 Toxicological Aspects
314(1)
15.4.3 Pharmacogenomics of Drug Transporters
315(1)
15.5 In Vitro Model Systems for Studying Renal Drug Transport
315(1)
15.6 FDA and EM A Draft Guidance/Guideline for Drug--Drug Interaction Studies
316(1)
15.7 Perspectives
316(11)
References
316(11)
16 Drug Transporters in the Intestine
327(14)
Patrick J. Sinko
16.1 Introduction
327(1)
16.2 Intestinal Drug Permeation
327(2)
16.2.1 Transcellular Diffusion
328(1)
16.2.2 Paracellular Transport
329(1)
16.2.3 Transcytosis
329(1)
16.3 Drug Transporters in the Small Intestine
329(2)
16.4 Impact of Small Intestinal Transporters on Oral Absorption of Drugs
331(4)
16.4.1 PepT1-Mediated Absorptive Transport
332(1)
16.4.2 OATP-Mediated Absorptive Transport
332(1)
16.4.3 P-gp-Mediated Secretory Transport
333(1)
16.4.4 BCRP-Mediated Secretory Transport
334(1)
16.4.5 Intestinal Basolateral Transporters
334(1)
16.5 Functional Modulation of Intestinal Transporters to Optimize Oral Absorption of Drugs
335(1)
16.6 Concluding Remarks
335(6)
References
335(6)
17 Drug Transport in the Placenta
341(14)
Qingcheng Mao
Vadivel Ganapathy
Jashvant D. Unadkat
17.1 Introduction
341(1)
17.2 Blood--Placental Barrier Relevant to Drug Permeability and Transport
341(1)
17.3 Drug Transporters in Human Placenta
342(6)
17.3.1 ABC Transporters in Human Placenta
342(3)
17.3.2 SLC Transporters in Human Placenta
345(3)
17.4 Methods to Study Placental Drug Transport
348(1)
17.5 Summary
349(6)
References
350(5)
18 Experimental Approaches to the Study of Drug Transporters
355(16)
Yoshiyuki Kubo
Akira Tsuji
Yukio Kato
18.1 Introduction
355(1)
18.2 In Vivo Experiments
355(3)
18.2.1 Preparation of Knockout Mice
355(1)
18.2.2 In Vivo RNA Interfrence
356(1)
18.2.3 Comparative Study of Wild-Type and Knockout/Knockdown Mice
356(1)
18.2.4 Humanized Mice
357(1)
18.2.5 In Vivo Imaging
358(1)
18.3 Isolated Tissue Methods
358(1)
18.3.1 Loop Method
358(1)
18.3.2 Ussing-Type Chamber
358(1)
18.3.3 Everted Sac Method
359(1)
18.3.4 Sliced Organs
359(1)
18.4 Primary Cell Cultures and Established Model Cell Lines
359(3)
18.4.1 Isolated Hepatocytes
359(1)
18.4.2 Fibroblasts
359(1)
18.4.3 Established Cell Lines
360(1)
18.4.4 Transfected Cell Lines and Xenopus laevis Oocytes
360(1)
18.4.5 Techniques to Study Cellular Uptake or Transport
361(1)
18.5 Membrane Vesicles
362(1)
18.5.1 Membrane Vesicles from Cultured Cells
362(1)
18.5.2 Membrane Vesicles from Tissues
362(1)
18.5.3 Rapid Filtration Technique
362(1)
18.6 Analysis of Drug Interaction Mechanisms
363(1)
18.6.1 Inhibition Studies
363(1)
18.6.2 Elucidation of Regulatory Mechanisms
363(1)
18.7 Perspectives
364(7)
References
365(6)
19 Transporters in Drug Discovery: In Silico Approaches
371(18)
Ayman El-Kattan
Manthena V. Varma
Yurong Lai
19.1 Introduction
371(1)
19.2 Physicochemical Determinants of Hepatobiliary Elimination
371(2)
19.3 In Silico Models for Biliary Excretion
373(2)
19.4 Physicochemical Determinants of Renal Elimination
375(1)
19.5 In Silico Models of Renal Excretion
375(1)
19.6 PhysiCochemical Determinants of Brain Penetration
376(1)
19.7 In Silico Approaches and SAR of Clinical Relevant Transporters
377(4)
19.7.1 MDR1 P-gp
377(1)
19.7.2 MRP2
378(1)
19.7.3 BCRP
379(1)
19.7.4 OATPs
380(1)
19.7.5 OATs and OCTs
381(1)
19.8 Strategies to Assess Transporter Involvement during Drug Discovery
381(1)
19.9 Conclusions
382(7)
References
382(7)
20 Polymorphisms of Drug Transporters and Clinical Relevance
389(20)
Aparna Chhibber
Janine Micheli
Deanna L. Kroetz
20.1 Genetic Variation and Drug Response
389(1)
20.2 Genetic Variation in Membrane Transporters
390(1)
20.3 Functional Analysis of Transporter Variants
391(3)
20.3.1 Coding Variants
391(2)
20.3.2 Noncoding Variants
393(1)
20.4 Clinical Significance of Transporter Variants
394(15)
20.4.1 Endogenous Substrates
394(2)
20.4.2 Drugs and Other Xenobiotic Substrates
396(1)
20.4.3 Future Directions
397(1)
References
398(11)
21 Diet/Nutrient Interactions with Drug Transporters
409(24)
Xiaodong Wang
Marilyn E. Morris
21.1 Introduction
409(1)
21.2 Diet/Nutrient Interactions with Drug Transporters
409(16)
21.2.1 Interactions of Diet/Dietary Supplements with Drug Transporters
409(7)
21.2.2 Interactions of Flavonoids with Drug Transporters
416(9)
21.3 Conclusions
425(8)
Acknowledgments
427(1)
References
427(6)
22 Clinical Relevance: Drug--Drug Interactions, Pharmacokinetics, Pharmacodynamics, and Toxicity
433(40)
Serena Marchetti
Jan H. M. Schellens
22.1 Introduction
433(1)
22.2 Interactions Mediated by ABC Drug Transporters
433(11)
22.2.1 ABCB1 (MDR1, P-Glycoprotein, Pgp)
433(5)
22.2.2 ABCG2 (Breast Cancer Resistance Protein, BCRP)
438(3)
22.2.3 ABCC Family (Multidrug Resistance-Associated Proteins, MRP1--MRP9)
441(3)
22.3 Interactions Mediated by Organic Anion and Cation Transporters (Solute Carrier Family, SLC22)
444(9)
22.3.1 Organic Anion Transporters (OATs)
444(2)
22.3.2 Organic Anion-Transporting Polypeptides (OATPs)
446(2)
22.3.3 Organic Cation Transporters (OCTs)
448(4)
22.3.4 Organic Cation/Ergothioneine/Carnitine Transporters (OCTNs)
452(1)
22.4 Interactions Mediated by Peptide Transporters (PEPTs, SLC15)
453(2)
22.4.1 Pharmacological and Toxicological Function
453(2)
22.4.2 Drug--Drug Interactions
455(1)
22.5 Interactions Mediated by Multidrug and Toxin Extrusion Transporters (MATEs, SLC47)
455(2)
22.5.1 Pharmacological and Toxicological Functions
455(1)
22.5.2 Drug--Drug Interactions
456(1)
22.6 Interactions Mediated by Monocarboxylate Transporters (MCTs, SLC16)
457(1)
22.6.1 Pharmacological and Toxicological Function
457(1)
22.6.2 Drug--Drug Interactions
458(1)
22.7 Interactions Mediated by Nucleoside (Concentrative and Equilibrative) Transporters (CNTs/ENTs, SLC28/29)
458(2)
22.7.1 Pharmacological and Toxicological Function
458(1)
22.7.2 Drug--Drug Interactions
459(1)
22.8 Conclusions
460(13)
References
461(12)
23 Regulatory Science Perspectives on Transporter Studies in Drug Development
473(18)
Sue-Chih Lee
Lei Zhang
Shiew-Mei Huang
23.1 Introduction
473(1)
23.2 Regulatory Science Perspectives on Transporter Studies
474(9)
23.2.1 The FDA Guidance on Evaluation of Transporter-Mediated Drug Interactions
474(1)
23.2.2 Overview of the FDA Guidance to Industry Pertaining to Transporters
475(3)
23.2.3 Emerging Transporters in Drug--Drug Interactions and Drug-Induced Toxicities
478(3)
23.2.4 Practical Considerations in Transporter Studies
481(2)
23.3 Recent FDA NDA Review Examples
483(3)
23.4 Conclusion and Future Directions
486(5)
Acknowledgments
486(1)
Abbreviation List
486(1)
References
487(4)
Index 491
Guofeng You is a Distinguished Professor of Pharmaceutics in the Ernest Mario School of Pharmacy at Rutgers University, USA. She has published numerous original research articles in the field of drug transport. She has been serving on several grant review panels of the National Institutes of Health and is on the editorial boards of leading journals. She was the coeditor for the first edition of this book (Wiley, 2007).

Marilyn E. Morris is Professor in the Department of Pharmaceutical Sciences  at the University at Buffalo, State University of New York. She is a Fellow of the American Association of Pharmaceutical Scientists (AAPS) and the American Association for the Advancement of Science (AAAS). and currently serves on the editorial boards of leading journals and was also co-editor for the first edition of this book (Wiley, 2007).