Оглавление
Группа авторов. Drug Transporters
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
DRUG TRANSPORTERS. Molecular Characterization and Role in Drug Disposition
LIST OF CONTRIBUTORS
PREFACE
1 OVERVIEW OF DRUG TRANSPORTER FAMILIES
1.1 INTRODUCTION
1.2 WHAT ARE DRUG TRANSPORTERS?
1.3 STRUCTURE AND MODEL OF DRUG TRANSPORTERS
1.4 TRANSPORT MECHANISMS
1.5 POLARIZED EXPRESSION OF DRUG TRANSPORTERS IN BARRIER EPITHELIUM
1.6 CLASSIFICATIONS OF DRUG TRANSPORTERS
1.6.1 Definition of Efflux and Influx Transporters
1.6.2 Definition of Absorptive and Secretory Transporters
1.6.3 Relationship Between Influx/Efflux and Absorptive/Secretory Transporters
1.6.4 ABC Transporters and SLC Transporters
1.7 NOMENCLATURE OF DRUG TRANSPORTERS
1.8 REGULATION OF DRUG TRANSPORTERS
1.9 CONCLUSION
REFERENCES
2 ORGANIC CATION AND ZWITTERION TRANSPORTERS
2.1 OVERALL INTRODUCTORY SECTION
CATION TRANSPORTERS: OCT1, OCT2, OCT3 (OTHER SECTION: SLC19A2, SLC19A3, PMAT) 2.2 INTRODUCTION TO THE OCT FAMILY
2.2.1 Tissue Distribution
2.2.2 Structure–Function Relationships
2.2.3 Transport Mechanism
2.3 OCT1. 2.3.1 Substrate and Inhibitor Selectivity
2.3.2 Regulation
2.3.3 Animal Models
2.3.4 Human Genetic Studies
2.3.5 Biomarkers and FDA Guidances for Transporter‐Mediated DDIs
2.4 OCT2. 2.4.1 Substrate and Inhibitor Selectivity
2.4.2 Regulation
2.4.3 Animal Models
2.4.4 Human Genetic Studies
2.5 OCT3. 2.5.1 Substrate and Inhibitor Selectivity
2.5.2 Regulation
2.5.3 Animal Models
2.5.4 Human Genetic Studies
2.6 OTHER IMPORTANT CATION TRANSPORTERS: SLC19A2, SLC19A3 (THIAMINE TRANSPORTERS), SLC29A4 (MONOAMINE TRANSPORTER) 2.6.1 Introduction
2.6.2 Tissue Distribution in Human
2.6.3 Substrate and Inhibitor Selectivity
2.6.4 Animal Models
2.6.5 Human Genetic Studies
ZWITTERION TRANSPORTERS: OCTN1, OCTN2, SLC22A15 AND SLC22A16 (OTHER SECTION: OCTN3) 2.7 INTRODUCTION TO THE ZWITTERION TRANSPORTERS
2.7.1 General Tissue Distribution
2.7.2 General Structure Function
2.7.3 Transport Mechanism
2.8 OCTN1. 2.8.1 Substrate and Inhibitor Selectivity
2.8.2 Regulation
2.8.3 Animal Models
2.8.4 Human Genetic Studies
2.9 OCTN2. 2.9.1 Substrate and Inhibitor Selectivity
2.9.2 Regulation
2.9.3 Animal Models
2.9.4 Human Genetic Studies
2.10 SLC22A15. 2.10.1 Introduction
2.10.2 Substrate and Inhibitor Selectivity
2.10.3 Human Genetic Studies
2.11 SLC22A16 (FLIPT2, CT2, OCT6) 2.11.1 Introduction
2.11.2 Substrate and Inhibitor Selectivity
2.11.3 Regulation
2.11.4 Human Genetic Studies
2.12 OCTN3. 2.12.1 Introduction
2.12.2 Substrate and Inhibitor Selectivity
2.12.3 Regulation
2.13 CONCLUSION
REFERENCES
3 MULTIDRUG AND TOXIN EXTRUSION PROTEINS
3.1 INTRODUCTION
3.2 TISSUE AND SUBCELLULAR DISTRIBUTION. 3.2.1 Tissue Distribution
3.2.2 Subcellular Localization
3.3 TRANSPORT ACTIVITY
3.3.1 Energetics of Transport
3.3.2 Substrates
3.3.2.1 Metformin
3.3.2.2 Platinum Drugs
3.3.2.3 Cardiovascular Drugs
3.3.2.4 Alkaloids
3.3.2.5 Paraquat
3.3.2.6 Endogenous Molecules
3.3.3 Inhibitors
3.4 STRUCTURE. 3.4.1 Modeling of Ligand Interactions
3.4.2 Secondary Structure
3.4.3 Structural Features
3.5 EXPRESSION AND REGULATION. 3.5.1 Transcriptional Regulation
3.5.2 Short‐Term Regulation
3.5.3 Sex and Age
3.5.4 Pregnancy
3.5.5 Disease Models. 3.5.5.1 Kidney Disease and Injury
3.5.5.2 Liver Disease and Injury
3.6 DRUG EFFICACY AND TOXICITY. 3.6.1 Clinical Substrates, Probes, and Inhibitors
3.6.2 Pharmacokinetic Drug Interactions
3.6.2.1 Metformin
3.6.2.2 Physiologically Based Pharmacokinetic Methods to Assess Interactions
3.6.2.3 Serum Creatinine and Kidney Function
3.6.2.4 Other Endogenous Probe SubstratesNMN has
3.7 PHARMACOGENETICS
3.7.1 Metformin Pharmacokinetics
3.7.2 Metformin Efficacy. 3.7.2.1 Diabetes
3.7.2.2 Nondiabetes Indications
3.7.3 Cisplatin Toxicity
3.7.4 Flutamide Liver Injury
3.8 CONCLUSIONS
ACKNOWLEDGMENT
REFERENCES
4 ORGANIC ANION TRANSPORTERS (OATs)
4.1 OAT FAMILY. 4.1.1 Introduction
4.1.2 Discovery
4.1.3 Nomenclature
4.2 MOLECULAR CHARACTERIZATION. 4.2.1 Genomics
4.2.2 Protein Structure
4.2.3 Mechanism of Substrate Translocation
4.3 EXPRESSION AND REGULATION OF OATS. 4.3.1 Tissue Distribution
4.3.2 Ontogeny
4.3.3 Transcriptional Regulation
4.3.4 Post‐translational Regulation
4.4 OAT SUBSTRATES AND DRUG–DRUG (DRUG–METABOLITE) INTERACTION. 4.4.1 Substrates
4.4.2 Substrate Specificity
4.4.3 Inhibitors
4.4.4 Natural Products and Herbal Medicines
4.4.5 Drug–Drug Interactions and Drug–Metabolite Interactions
4.5 SYSTEMS BIOLOGY OF OATS. 4.5.1 Physiological Role
4.5.2 Metabolic Pathways Regulated by OATs
4.5.3 Chronic Kidney Disease and Uremic Toxins
4.5.4 Pathophysiology
4.5.5 Clinical Pharmacology
4.5.6 Remote Sensing and Signaling Theory
4.6 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
5 ORGANIC ANION TRANSPORTING POLYPEPTIDES OATP
5.1 INTRODUCTION TO THE OATP SUPERFAMILY
5.1.1 Nomenclature
5.2 MOLECULAR CHARACTERISTICS OF OATPS
5.2.1 Protein Structure
5.2.2 Transport Mechanisms
5.3 EXPRESSION AND REGULATION OF OATPS. 5.3.1 Tissue Distribution
5.3.2 Ontogeny of Expression
5.3.3 Post‐Translational Regulation. 5.3.3.1 Phosphorylation
5.3.3.2 N‐Glycosylation
5.3.3.3 Adapter Protein Interactions
5.3.4 Transcriptional Regulation
5.3.4.1 Liver‐Enriched Transcription Factors
5.3.4.2 Farnesoid X Receptor
5.3.4.3 Liver X Receptor
5.3.4.4 Pregnane X Receptor
5.3.4.5 Vitamin D Receptor
5.3.4.6 Thyroid Hormone Receptor
5.3.4.7 Aryl Hydrocarbon Receptor
5.3.4.8 Hypoxia‐Inducible Factor 1
5.3.4.9 Wnt‐β‐Catenin Signaling
5.3.4.10 Inflammatory Cytokine Signaling
5.3.5 Epigenetic Regulation. 5.3.5.1 Promoter Methylation
5.3.5.2 Micro‐RNA Regulation
5.4 OATP SUBSTRATES, INHIBITORS, AND STIMULATORS. 5.4.1 Substrates
5.4.2 Inhibitors
5.4.3 Stimulators
5.5 PHARMACOLOGY OF OATPS. 5.5.1 Role of OATPs in Drug Disposition
5.5.2 In vitro and In vivo OATP Probe Substrates and Inhibitors
5.5.3 Endogenous Biomarkers of OATP Activity
5.5.4 PET, SPECT, and MR Imaging Markers
5.5.5 Drug, Food, and Formulation Interactions
5.5.6 Pharmacogenetics
5.5.6.1 SLCO1B1
5.5.6.2 SLCO1B3
5.5.6.3 SLCO1A2
5.5.6.4 SLCO2B1
5.5.7 Effects of Disease on OATP Expression and Activity
5.5.7.1 Liver Cirrhosis
5.5.7.2 Nonalcoholic Fatty Liver Disease
5.5.7.3 Cholestatic Liver Disease
5.5.7.4 Chronic Kidney Disease
5.5.7.5 Inflammatory Diseases
5.6 PHYSIOLOGY AND PATHOPHYSIOLOGY OF OATPS. 5.6.1 Bilirubin Homeostasis
5.6.2 Bile Acid Homeostasis
5.6.3 Thyroid Hormones Homeostasis
5.6.4 Prostaglandins Homeostasis
5.6.5 Steroid Hormone Homeostasis
5.6.6 Cancers
5.6.6.1 Breast Cancer
5.6.6.2 Gastrointestinal Cancers
5.6.6.3 Prostate Cancer
5.6.7 Cardiovascular Disease
5.7 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
6 MAMMALIAN OLIGOPEPTIDE TRANSPORTERS
6.1 INTRODUCTION
6.1.1 Peptide and Protein Permeation Routes Across the GI Epithelium
6.2 OLIGOPEPTIDE TRANSPORTERS
6.2.1 Molecular and Structural Characteristics of Oligopeptide Transporters
6.3 FUNCTIONAL PROPERTIES. 6.3.1 Mechanism of Transport
6.3.2 Molecular Requirements for Substrate Recognition and Transport
6.3.3 General Substrate Specificities
6.3.4 Established Endogenous and Exogenous Substrates
6.4 REGULATION
6.4.1 Dietary Regulation
6.4.2 Developmental Regulation
6.4.3 Regulation by Circadian Rhythms
6.4.4 Disease State‐Dependent Regulation
6.4.5 Hormonal Regulation
6.4.6 Regulation by Pharmaceutical Agents
6.4.7 Single Nucleotide Polymorphisms
6.4.8 Splice Variants
6.5 PHARMACEUTICAL DRUG SCREENING
6.5.1 Case Study: Targeting Peptide Transporters for Increased Oral Absorption: Valacyclovir
6.6 CONCLUDING REMARKS
REFERENCES
7 MONOCARBOXYLIC ACID TRANSPORTERS
7.1 INTRODUCTION
7.2 SLC5 TRANSPORTER FAMILY. 7.2.1 Structure, Function, Localization, and Substrates. 7.2.1.1 Structure
7.2.1.2 Localization and Function
7.2.2 Regulation
7.2.3 Role in Health and Disease
7.2.4 Role in Drug Disposition
7.3 SLC16 TRANSPORTER FAMILY. 7.3.1 Structure, Function, Localization, and Substrates. 7.3.1.1 Structure and Function
7.3.1.2 Localization and Substrates
7.3.2 Regulation. 7.3.2.1 Transcriptional Regulation
7.3.2.2 Epigenetic Regulation
7.3.2.3 Post‐Transcriptional Regulation
7.3.2.4 Membrane Trafficking Regulation
7.3.2.5 Regulation of Transporter Activity
7.3.3 Role in Health and Disease. 7.3.3.1 Monocarboxylate Transporters 1, 2, and 4 (SLC16A1, SLC16A7, SLC16A3)
7.3.3.2 Monocarboxylate Transporter 3 (SLC16A8)
7.3.3.3 Monocarboxylate Transporter 5 (SLC16A4)
7.3.3.4 Monocarboxylate Transporter 6 (SLC16A5)
7.3.3.5 Monocarboxylate Transporter 7 (SLC16A6)
7.3.3.6 Monocarboxylate Transporter 8 (SLC16A2)
7.3.3.7 Monocarboxylate Transporter 9 (SLC16A9)
7.3.3.8 Monocarboxylate Transporter 10 (SLC16A10)
7.3.3.9 Monocarboxylate Transporter 11 (SLC16A11)
7.3.3.10 Monocarboxylate Transporter 12 (SLC16A12)
7.3.3.11 Monocarboxylate Transporter 13/14 (SLC16A13/SLC16A14)
7.3.4 Role in Drug Disposition
7.3.4.1 Role of MCTs in the Disposition of GHB
7.3.4.2 Role of MCTs in the Disposition of Other Drugs
7.4 CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES
8 THE NUCLEOSIDE TRANSPORTERS CNTs AND ENTs
8.1 INTRODUCTION
8.2 MOLECULAR AND FUNCTIONAL CHARACTERISTICS OF CNTs (SLC28) 8.2.1 Family Members and Substrate Specificity of CNTs
8.2.2 Transport Mode of CNTs
8.2.3 Tissue Distribution and Cellular Localization of CNTs
8.2.4 Interaction with Nucleoside Analogs
8.2.5 Structure–Function Relationship of CNTs
8.3 MOLECULAR AND FUNCTIONAL CHARACTERISTICS OF ENTs (SLC29) 8.3.1 Family Members and Substrate Specificity of ENTs
8.3.2 Transport Mode of ENTs
8.3.3 Tissue Distribution and Cellular Localization of ENTs
8.3.4 Interaction with Nucleoside Analogs
8.3.5 Structure–Function Relationship of ENTs
8.4 METHODS AND MOUSE MODELS TO STUDY ENTs AND CNTs
8.5 REGULATION OF CNTs AND ENTs
8.6 PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL FUNCTIONS OF CNTs AND ENTs. 8.6.1 Nucleoside Homeostasis
8.6.2 Adenosine Signaling
8.6.3 ENTs and CNTs in AMPK Signaling
8.6.4 ENT1 and ENT3 in Hematopoiesis/Erythropoiesis
8.6.5 ENT3 in Autosomal Recessive Disorders
8.6.6 CNT1 in Inherited Metabolic Disorders
8.7 THERAPEUTIC SIGNIFICANCE OF CNTs AND ENTs
8.7.1 CNTs and ENTs in Intracellular Disposition of Nucleoside Drugs
8.7.2 CNTs and ENTs in Pharmacokinetics of Nucleoside Drugs
8.7.3 CNTs and ENTs as Drug Targets
8.8 CONCLUSIONS
ACKNOWLEDGMENT
REFERENCES
9 BILE ACID TRANSPORTERS
9.1 INTRODUCTION
9.2 OVERVIEW OF TRANSPORTERS IN THE ENTEROHEPATIC CIRCULATION OF BILE ACIDS
9.3 HEPATOBILIARY BILE ACID TRANSPORTERS. 9.3.1 BSEP/ABCB11: Bile Salt Export Pump
9.3.2 NTCP/SLC10A1: Sodium Taurocholate Cotransporting Polypeptide
9.4 INTESTINAL BILE ACID TRANSPORTERS. 9.4.1 ASBT/SLC10A2: Apical Sodium‐Dependent Bile Acid Transporter
9.4.2 OSTα‐OSTβ/SLC51A/SLC51B: The Basolateral Heteromeric Organic Solute Transporter
9.5 CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES
10 THE P‐GLYCOPROTEIN MULTIDRUG TRANSPORTER
10.1 MULTIDRUG RESISTANCE AND P‐GLYCOPROTEIN
10.2 EXPRESSION PATTERN OF P‐GLYCOPROTEIN
10.3 SUBSTRATES AND INHIBITORS OF P‐GLYCOPROTEIN
10.4 STRUCTURE OF P‐GLYCOPROTEIN
10.5 EPITOPE MAPPING OF MONOCLONAL ANTIBODIES SPECIFIC FOR HUMAN P‐GLYCOPROTEIN (MRK‐16, 4E3, AND UIC2)
10.6 MOLECULAR MECHANISM OF POLYSPECIFICITY
10.7 DRUG TRANSPORT CYCLE OF P‐GLYCOPROTEIN
10.8 EFFORTS TO DISCOVER MODULATORS
10.9 ROLE OF P‐GLYCOPROTEIN IN THE PHYSIOLOGY AND BIOAVAILABILITY OF DRUGS
10.10 CONCLUSIONS AND FUTURE PERSPECTIVE
ACKNOWLEDGMENTS
REFERENCES
11 MULTIDRUG RESISTANCE PROTEINS OF THE ABCC SUBFAMILY
11.1 INTRODUCTION
11.2 NOMENCLATURE AND MOLECULAR CHARACTERIZATION
11.3 EXPRESSION AND LOCALIZATION OF ABCC TRANSPORTERS IN NORMAL HUMAN TISSUES AND IN HUMAN CANCERS
11.4 FUNCTIONAL PROPERTIES/SUBSTRATE SPECIFICITY AND MULTIDRUG RESISTANCE PROFILES OF HUMAN ABCC/MRPS
11.5 CLINICAL CONSEQUENCES OF GENETIC VARIANTS IN ABCC GENES
11.5.1 Genetic Variants of Human ABCC/MRP Genes and the Mendelian Inheritance of Diseases and Syndromes
11.5.1.1 ABCC2/MRP2 and Dubin–Johnson Syndrome
11.5.1.2 ABCC6/MRP6 and Pseudoxanthoma Elasticum
11.5.1.3 ABCC11/MRP8 and Earwax type
11.5.2 Genetic Variants of Human ABCC/MRP Genes and Clinical Consequences on Drug Response and Susceptibility to Complex Disease. 11.5.2.1 ABCC1/MRP1
11.5.2.2 ABCC2/MRP2
11.5.2.3 ABCC3/MRP3
11.5.2.4 ABCC4/MRP4
11.5.2.5 ABCC5/MRP5
11.5.2.6 ABCC6/MRP6
11.5.2.7 ABCC10/MRP7
11.5.2.8 ABCC11/MRP8
11.6 CONCLUSION
ACKNOWLEDGMENTS
REFERENCES
12 ABCG2, THE BREAST CANCER RESISTANCE PROTEIN (BCRP)
12.1 DISCOVERY AND NOMENCLATURE
12.2 THE ABCG2 GENE AND EXPRESSION. 12.2.1 The ABCG2 Gene
12.2.2 Factors Controlling ABCG2 Expression
12.3 PHYSICAL PROPERTIES. 12.3.1 Structure
12.3.2 Trafficking and Regulation of Cell Surface Expression
12.4 SUBSTRATES AND INHIBITORS OF BCRP. 12.4.1 Endogenous Substrates
12.4.2 Exogenous Substrates
12.4.3 Inhibitors
12.5 RECENT FINDINGS CONCERNING PHYSIOLOGICAL FUNCTIONS. 12.5.1 ABCG2, Urate, and Gout
12.5.2 Jr(a‐) Phenotype
12.6 PREDICTED PHYSIOLOGICAL FUNCTION FROM TISSUE DISTRIBUTION
12.6.1 Stem Cells
12.6.2 Placenta
12.6.3 Mammary Gland
12.6.4 Testis
12.6.5 Blood–Brain Barrier
12.6.6 Liver and the Gastrointestinal Tract
12.6.7 Kidneys
12.7 ABCG2 EXPRESSION IN CANCER AND ITS ROLE IN DRUG RESISTANCE
12.8 GENETIC POLYMORPHISMS
12.8.1 Genetic Variants of ABCG2
12.8.2 The Q141K (rs2231142) SNP and Drug Disposition/Clinical Outcome
12.8.3 Other ABCG2 Polymorphisms and Drug Disposition/Clinical Outcome
12.9 CONCLUSION
REFERENCES
13 DRUG TRANSPORT IN THE LIVER
13.1 INTRODUCTION
13.2 HEPATIC PHYSIOLOGY: LIVER STRUCTURE AND FUNCTION
13.3 HEPATIC TRANSPORT PROTEINS
13.3.1 Uptake Transporters
13.3.2 Canalicular (Apical) Efflux Transporters
13.3.3 Basolateral Efflux Transporters
13.4 REGULATION OF HEPATIC TRANSPORT PROTEINS IN HUMANS
13.4.1 Transcriptional Regulation
13.4.2 Post‐Translational Regulation
13.4.3 Transporter Induction
13.5 PHYSIOLOGICAL FACTORS THAT INFLUENCE HEPATIC DRUG TRANSPORT PROTEINS IN HUMANS. 13.5.1 Ontogeny and Effects of Aging on Hepatic Transporters
13.5.2 Microbiome Effects on Hepatic Transporters
13.6 DISEASE‐RELATED ALTERATIONS IN HUMAN HEPATIC TRANSPORT PROTEINS
13.6.1 Hepatic Transporter‐Mediated Liver Diseases
13.6.1.1 Cholestatic Disorders
13.6.1.2 Dubin–Johnson Syndrome
13.6.1.3 Rotor Syndrome
13.6.2 Liver Disease‐Mediated Alterations in Hepatic Transporters
13.6.2.1 Cholestasis
13.6.2.2 Nonalcoholic Fatty Liver Disease
13.6.2.3 Cirrhosis
13.6.2.4 Hepatocellular Carcinoma
13.6.2.5 Autoimmune Hepatitis
13.6.2.6 Alcoholic Liver Disease
13.6.2.7 Chronic Hepatitis C Viral Infection
13.6.3 Other Non‐Hepatic Disease‐Mediated Alterations in Hepatic Transporters. 13.6.3.1 Renal Diseases
13.6.3.2 Sepsis/Acute Inflammation
13.7 METHODS FOR STUDYING HEPATOBILIARY DRUG TRANSPORT
13.7.1 In vitro Systems
13.7.2 In vivo Systems
13.7.3 In silico Approaches
13.8 HEPATIC TRANSPORTER‐MEDIATED DRUG–DRUG INTERACTIONS (DDIS)
13.9 INTERPLAY BETWEEN DRUG METABOLISM AND TRANSPORT
13.10 HEPATIC TRANSPORT PROTEINS AS DETERMINANTS OF DRUG TOXICITY
13.11 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. 14.2.1 Blood–Brain Barrier/Neurovascular Unit
14.2.1.1 Endothelial Cells
14.2.1.2 Pericytes
14.2.1.3 Astrocytes
14.2.1.4 Neurons
14.2.1.5 Other Glial Cells in the Brain Parenchyma (Oligodendrocytes, Microglia)
14.2.2 Blood–Cerebrospinal Fluid Barrier
14.2.3 Blood–Arachnoid Barrier
14.3 FUNCTIONAL EXPRESSION AND LOCALIZATION OF DRUG TRANSPORTERS IN THE BRAIN. 14.3.1 ABC Transporters
14.3.1.1 P‐glycoprotein (P‐gp)
14.3.1.2 Breast Cancer Resistance Protein (BCRP/Bcrp)
14.3.1.3 Multidrug Resistance Proteins (MRPs/Mrps)
14.3.2 Solute Carrier (SLC) Transporter Family
14.3.2.1 Organic Cation Transporters (OCTs/Octs) and Novel Organic Cation Transporters (OCTNs/Octns)
14.3.2.2 Organic Anion Transporters (OATs)
14.3.2.3 Organic Anion Transporting Polypeptides (OATPs/Oatps)
14.3.2.3.1 Human OATP Isoforms
14.3.2.3.2 Rodent Oatp Isoforms
14.3.2.4 Peptide Transporters
14.3.2.5 Nucleoside Transporters. 14.3.2.5.1 Concentrative Nucleoside Transporters (CNTs)
14.3.2.5.2 Equilibrative Nucleoside Transporters (ENTs)
14.3.2.6 Folate Receptors/Transporters
14.3.2.6.1 Folate Receptors
14.3.2.6.2 Reduced Folate Carrier
14.3.2.6.3 Proton‐Coupled Folate Transporter
14.4 RELEVANCE OF DRUG TRANSPORTERS IN CNS DISORDERS. 14.4.1 HIV‐1 Infection of the Brain
14.4.2 Neurodegenerative Disorders. 14.4.2.1 Parkinson’s Disease
14.4.2.2 Alzheimer’s Disease
14.4.2.3 Multiple Sclerosis
14.4.3 Epilepsy
14.4.4 Brain Neoplasia
14.4.5 Cerebral Hypoxia and Ischemic Stroke
14.4.6 Traumatic Brain Injury
14.4.7 Pain
14.4.8 Cerebral Folate Deficiency Disorders
14.5 CONCLUSION
REFERENCES
15 DRUG TRANSPORT IN THE KIDNEY
15.1 KIDNEY STRUCTURE AND FUNCTION
15.2 MAJOR DRUG TRANSPORTERS EXPRESSED IN HUMAN KIDNEY
15.3 TARGETED PROTEOMICS OF HUMAN RENAL TRANSPORTERS
15.4 HUMAN TRANSPORTERS IN RENAL INJURY AND DISEASE. 15.4.1 Ischemia/Reperfusion Injury
15.4.2 Glucose Transporters and Diabetes
15.4.3 Chronic Kidney Disease
15.4.4 Hyperuricemia and Gout
15.5 CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES
16 DRUG TRANSPORTERS IN THE HUMAN INTESTINE
16.1 INTRODUCTION
16.2 INTESTINAL ABC TRANSPORTERS (EXPRESSION, LOCALIZATION, FUNCTION)
16.3 INTESTINAL SLC TRANSPORTERS (EXPRESSION, LOCALIZATION, FUNCTION)
16.4 INTERPLAY OF APICAL AND BASOLATERAL TRANSPORTERS
16.5 VARIABILITY OF INTESTINAL TRANSPORTERS
16.5.1 Transcriptional Regulation by Nuclear Receptors
16.5.2 Epigenetic Regulation
16.5.3 Disease‐Related Changes
16.6 DRUG–DRUG INTERACTIONS INVOLVING INTESTINAL TRANSPORTERS
16.7 LIMITATIONS OF AVAILABLE RESEARCH MODELS FOR THE HUMAN INTESTINE
16.8 CONCLUSIONS AND FUTURE PERSPECTIVES
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
17.3.1 ABC Transporters in Human Placenta. 17.3.1.1 P‐glycoprotein (P‐gp, MDR1, or ABCB1)
17.3.1.2 Breast Cancer Resistance Protein (BCRP or ABCG2)
17.3.1.3 Multidrug Resistance Proteins (MRPs or ABCCs)
17.3.2 SLC Transporters in Human Placenta. 17.3.2.1 Monoamine Transporters
17.3.2.2 Organic Cation and Anion Transporters
17.3.2.3 Organic Anion Transporting Polypeptides (OATPs)
17.3.2.4 Monocarboxylate Transporters MCT1 (SLC16A1) and MCT4 (SLC16A3)
17.3.2.5 Folate Transporters RFT1 (SLC19A1) and PCFT (SLC46A1)
17.3.2.6 Equilibrative Nucleoside Transporters
17.4 METHODS TO STUDY PLACENTAL DRUG TRANSPORT
17.5 CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES
18 POLYMORPHISMS OF DRUG TRANSPORTERS AND CLINICAL RELEVANCE
18.1 INTRODUCTION
18.2 GENETIC VARIATION IN DRUG TRANSPORTERS LEADING TO ALTERED EFFECT
18.2.1 ABCB1 (MDR1, P‐Glycoprotein)
18.2.2 ABCG2 (BCRP, Breast Cancer Resistance Protein)
18.2.3 SLCO1B1 (OATP1B1, Organic Anion Transporter Polypeptide 1B1)
18.2.4 SLC22A1 (OCT1, Organic Cation Transporter 1)
18.2.5 SLC22A2 (OCT2, Organic Cation Transporter 2)
18.2.6 SLC47A1/SLC47A2 (MATE1/MATE2‐K, Multidrug and Toxin Extrusion Protein 1/2‐K)
18.2.7 SLC22A6/SLC22A8 (OAT1/OAT3, Organic Anion Transporter 1/3)
18.3 DISCUSSION
18.4 PERSPECTIVES
REFERENCES
19 ONTOGENY OF DRUG TRANSPORTERS
19.1 INTRODUCTION
19.1.1 Pediatric Populations
19.1.2 Assessment of Ontogeny
19.2 TRANSPORTER ONTOGENY
19.2.1 Liver. 19.2.1.1 ABC Transporters. 19.2.1.1.1 Breast Cancer Resistance Protein (BCRP)
19.2.1.1.2 Bile Salt Export Pump (BSEP)
19.2.1.1.3 Multidrug Resistance Protein (MRP)
19.2.1.1.4 P‐Glycoprotein (PGP)
19.2.1.2 SLC Transporters. 19.2.1.2.1 Multidrug and Toxin Extrusion (MATE)
19.2.1.2.2 Monocarboxylate Transporters (MCTs)
19.2.1.2.3 Organic Anion Transporters (OATs)
19.2.1.2.4 Organic Anion Transporting Polypeptides (OATPs)
19.2.1.2.5 Organic Cation Transporters (OCTs)
19.2.1.2.6 Organic Cation Transporter Novel (OCTN)
19.2.1.2.7 Organic Solute Transporter (OST)
19.2.1.2.8 Sodium/Taurocholate Cotransporting Polypeptide (NTCP)
19.2.2 Intestine. 19.2.2.1 ABC Transporters. 19.2.2.1.1 BCRP
19.2.2.1.2 MRPs
19.2.2.1.3 PGP
19.2.2.2 SLC Transporters. 19.2.2.2.1 Apical Sodium Dependent Bile Acid Transporter (ASBT)
19.2.2.2.2 OATP
19.2.2.2.3 OCT
19.2.2.2.4 OSTα/β
19.2.2.2.5 Peptide Transporters (PEPT)
19.2.3 Kidney. 19.2.3.1 ABC Transporters. 19.2.3.1.1 BCRP
19.2.3.1.2 MRPs
19.2.3.1.3 PGP
19.2.3.2 SLC Transporters. 19.2.3.2.1 MATE
19.2.3.2.2 OATs
19.2.3.2.3 OATPs
19.2.3.2.4 OCTs
19.2.3.2.5 OCTNs
19.2.3.2.6 PEPT
19.3 CHALLENGES IN ASSESSING TRANSPORTER ONTOGENY
19.4 CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES
20 EXPERIMENTAL APPROACHES FOR STUDYING DRUG TRANSPORTERS
20.1 INTRODUCTION
20.2 GENETICALLY MODIFIED AND HUMAN‐XENOGRAFT MODEL ANIMALS. 20.2.1 Gene Knockout Rodents
20.2.2 Transient Knockdown Rodents
20.2.3 Genetically Humanized Mice
20.2.4 Human Organ Xenograft Mice
20.3 IN VIVO EXPERIMENTS
20.3.1 Pharmacokinetic Analysis
20.3.2 Integration Plot Analysis
20.3.3 Imaging Analysis
20.3.4 Metabolome Analysis
20.3.5 Microdialysis
20.4 ISOLATED TISSUE METHODS
20.4.1 Transport Studies in Intestinal Tissues. 20.4.1.1 The Loop Method
20.4.1.2 The Ussing‐Type Chamber Method
20.4.1.3 The Everted Sac Method
20.4.2 Sliced Organs
20.4.3 Perfused Organs
20.5 PRIMARY CELL CULTURES, ESTABLISHED MODEL CELL LINES, AND THEIR COMBINATION
20.5.1 Cryopreserved and Freshly Isolated Hepatocytes
20.5.2 Isolated Renal Proximal Tubule Cells
20.5.3 Established Cell Lines
20.5.4 Conditionally Immortalized Cell Lines
20.5.5 iPS Cells
20.5.6 Heterologous Expression of Drug Transporters in Immortalized Cell Lines
20.5.7 Heterologous Expression of Drug Transporters in Xenopus laevis Oocytes
20.5.8 Microphysiological System
20.6 ANALYSIS OF THE TRANSPORT, INHIBITION, INDUCTION, AND DOWNREGULATION OF TRANSPORTERS
20.6.1 Uptake Studies in Cultured Cells
20.6.2 Transcellular Transport Studies
20.6.3 Analysis of the Direct Inhibition of Transporters
20.6.4 Assay of Preincubation‐Dependent and Long‐Lasting Inhibition
20.6.5 Induction and Downregulation of Transporters
20.6.6 Quantification of Transporter Protein Expression
20.6.7 Screening of Transporters Based on a Genetic Approach
20.7 MEMBRANE VESICLES
20.7.1 Preparation of Membrane Vesicles from Tissues
20.7.2 Preparation of Membrane Vesicles from Gene Expression Systems
20.7.3 Purification and Reconstitution of Transporters
20.7.4 Methods in Transport Studies Using Membrane Vesicles
20.8 PERSPECTIVES
REFERENCES
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. 21.7.1 P‐glycoprotein (P‐gp)
21.7.2 Multidrug Resistance Associated Protein 2 (MRP2)
21.7.3 Breast Cancer Resistant Protein (BCRP)
21.7.4 Organic Anion Transporting Polypeptide Transporters (OATPs)
21.7.5 Organic Anion Transporters (OATs) and Organic Cation Transporters (OCTs)
21.8 STRATEGIES TO ASSESS TRANSPORTER INVOLVEMENT DURING DRUG DISCOVERY
21.9 TARGETING DRUG TRANSPORTERS: CASE EXAMPLES. 21.9.1 Design of Hepatoselective Agent—Targeting OATP1B1/1B3
21.9.2 Intestine‐Specific P‐glycoprotein Inhibitor
21.10 CONCLUSIONS
REFERENCES
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
22.2.1 Contribution of Each Transporter to the Overall Membrane Transport
22.2.2 Analysis of the Rate‐Determining Process in the Hepatic Elimination Clearance of Drugs Based on the Extended Clearance Concept
22.2.3 Relationship Between the Overall Intrinsic Organ Clearance and Organ Clearance
22.3 PREDICTION OF HEPATIC TRANSPORT FROM IN VITRO DATA. 22.3.1 Prediction of Hepatic Uptake Clearance from In Vitro Experiments with Hepatocytes
22.3.2 “Albumin‐Mediated” Hepatic Uptake Mechanism: Importance in the In Vitro–In Vivo Extrapolation of Hepatic Uptake Clearance
22.3.3 Prediction of Biliary Excretion Clearance
22.4 PREDICTION OF RENAL TRANSPORT FROM IN VITRO DATA
22.5 PREDICTION OF TRANSPORTER‐MEDIATED DRUG–DRUG INTERACTIONS FROM IN VITRO DATA. 22.5.1 Background Theory
22.5.2 Possible Cause for the Discrepancy of In Vitro and In Vivo Kinetic Parameters Used for the Estimation of DDI Risks
22.5.3 Prediction of Complex DDIs by In Vitro Data and PBPK Models Utilizing the “Middle‐Out” Approach
22.6 CONCLUSIONS AND PERSPECTIVES
REFERENCES
23 APPLICATION OF PHYSIOLOGICALLY BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODELING COMPRISING TRANSPORTERS: DELINEATING THE ROLE OF VARIOUS FACTORS IN DRUG DISPOSITION AND TOXICITY
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
23.2.1 PBPK Model Principles (A focused appraisal of core principles related to PBPK models that include transporters)
23.2.2 Modeling Permeability‐Limited Organ Models
23.2.2.1 General Concepts and Considerations of Permeability‐Limited Organ Modeling
23.2.2.2 Permeability‐Limited Liver Modeling
23.2.2.3 Permeability‐Limited Kidney Modeling
23.2.2.4 Permeability‐Limited Models for the Intestine
23.2.2.5 Permeability‐Limited Brain Models
23.2.2.6 Other Organs for Consideration for Permeability‐Limited Application
23.3 REAL‐WORLD APPLICATIONS OF TRANSPORTER ACTIVITY IN PBPK MODELS
23.3.1 Application I—Simultaneous Assessment of Transporters and Enzymes Impacting on Oral Bioavailability Using PBPK
23.3.2 Application II—Factoring in Metabolites When Considering Simultaneous Transporter‐Mediated DDIs
23.3.3 Application III—Addressing Population Variability for Combined Enzyme and Transporter‐Mediated Disposition: Application of Models for Disease Populations
23.3.4 Application IV—Extending Transporter Models—A Case for Applying Electrochemical Gradient Approach to Address Transporter Functionality
23.3.5 Application V—Toxicity
23.3.6 Application VI—Pharmacodynamics (Including Untangling the Impact of Transporters on the Variability of Pharmacokinetics versus Pharmacodynamics)
23.4 CONCLUSIONS AND FUTURE PERSPECTIVES
REFERENCES
24 TRANSPORTERS AS THERAPEUTIC TARGETS IN HUMAN DISEASES
24.1 INTRODUCTION
24.2 SLC TRANSPORTERS IN DISEASE AS TARGETS AND MODULATORS. 24.2.1 SLC Transporters as Targets in Cancer
24.2.1.1 Targeting Transporters with Imaging Agents in Cancer
24.2.2 SLC Transporters as Targets in Neurological Diseases
24.2.2.1 Major Depressive Disorder
24.2.2.2 Amyotrophic Lateral Sclerosis
24.2.2.3 Schizophrenia
24.2.2.4 Pain
24.2.3 SLC Transporters as Targets in Cardiovascular Disease, Hypertension, and Metabolic Diseases. 24.2.3.1 Cardiovascular Disease and Hypertension
24.2.3.2 Metabolic Diseases
24.3 ABC TRANSPORTERS IN DISEASE AS TARGETS AND MODULATORS. 24.3.1 ABC Transporters in Cancer as Modulators and Targets
24.3.2 ABC Transporters as Targets in Neurological Diseases
24.3.2.1 Alzheimer’s Disease
24.3.2.2 X‐Linked Adrenoleukodystrophy (X‐ALD)
24.4 CONCLUSIONS AND FUTURE PERSPECTIVES
ACKNOWLEDGMENTS
REFERENCES
25 DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS
25.1 INTRODUCTION
25.2 DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS. 25.2.1 Interactions of Diet/Dietary Supplements with Drug Transporters
25.2.1.1 St. John’s Wort
25.2.1.1.1 Effects on Drug Transporters
25.2.1.1.2 Clinical Drug Interactions
25.2.1.2 Grapefruit Juice
25.2.1.2.1 Effects on Drug Transporters
25.2.1.2.2 Clinical Drug Interactions
25.2.1.3 Green Tea
25.2.1.3.1 Effects on Drug Transporters
25.2.1.3.2 Clinical Drug Interactions
25.2.1.4 Ginseng
25.2.1.5 Turmeric
25.2.1.6 Red Wine
25.2.1.7 Ginkgo
25.2.2 Interactions of Flavonoids with Drug Transporters
25.2.2.1 Interactions with P‐gp
25.2.2.2 Interactions with MRPs
25.2.2.3 Interactions with BCRP
25.2.2.4 Interactions with OATP
25.2.2.5 Interactions with OAT
25.2.3 Interactions of Isothiocyanates with Drug Transporters
25.3 CONCLUSIONS
ACKNOWLEDGMENTS
REFERENCES
INDEX
Wiley Series in Drug Discovery and Development
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