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Albert P. Li
Transporters and Drug-Metabolizing Enzymes in Drug Toxicity
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Страница 1
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
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1 Overview: Drug Metabolism, Transporter‐Mediated Uptake and Efflux, and Drug Toxicity
1.1 Drug Toxicity as a Challenge in Drug Development
1.2 Fate of an Orally Administered Drug
1.3 The Multiple Determinant Hypothesis for Idiosyncratic Drug Toxicity
1.4 Concluding Remarks
1.4.1 A Comprehensive Approach to Safety Evaluation in Drug Development
1.4.2 The Dose Makes the Poison – Paracelsus Updated
References
2 Transporter, Drug Metabolism, and Drug‐Induced Liver Injury in Marketed Drugs
2.1 Introduction
2.2 Hepatic Metabolism
2.2.1 Phase I Metabolism
2.2.2 Phase II Metabolism
2.3 Reactive Metabolite Formation and Assessment
2.3.1 Metabolism and Reactive Metabolites
2.3.2 Dose and Reactive Mtabolites
2.3.3 Structural Alerts for Avoiding Reactive Metabolites
2.3.4 Experimental Approaches for Assessing Reactive Metabolites
2.3.4.1 Covalent Binding Assay
2.3.4.2 Electrophile Trapping Experiments
2.3.4.3 Time Dependent Inactivation of CYP450 Enzymes
2.4 Hepatic Transporters
2.5 Genetic Variants and Their Impact for Pharmacokinetic Behavior and Safety
2.5.1
CYP3A4
2.5.2
CYP3A5
2.5.3
CYP2D6
2.5.4
CYP2C9
2.5.5
CYP2C19
2.5.6
CYP2B6
2.5.7
UGT1A1
2.5.8 NAT2
2.5.9 Hepatic Transporters
2.6 Summary
Acknowledgment
Disclaimer
References
3 Drug‐Metabolism Enzymes and Transporter Activities as Risk Factors of Selected Marketed Drugs Associated with Drug‐Induced Fatalities
3.1 Introduction
3.2 Acetaminophen
3.2.1 Drug Metabolism and Toxicity
3.2.2 Transporters and Toxicity
3.2.3 Risk Factors
3.3 Cerivastatin
3.3.1 Drug Metabolism and Toxicity
3.3.2 Transporter and Toxicity
3.3.3 Risk Factors
3.4 Felbamate
3.4.1 Drug Metabolism and Toxicity
3.4.2 Transporters and Toxicity
3.4.3 Risk Factors
3.5 Flucloxacillin
3.5.1 Drug Metabolism and Toxicity
3.5.2 Transporters and Toxicity
3.5.3 Risk Factors
3.6 Nefazodone
3.6.1 Drug Metabolism and Toxicity
3.6.2 Transporters and Toxicity
3.6.3 Risk Factors
3.7 Obeticholic Acid
3.7.1 Drug Metabolism and Toxicity
3.7.2 Transporters and Toxicity
3.7.3 Risk Factors
3.8 Sitaxentan
3.8.1 Drug Metabolism and Toxicity
3.8.2 Transporters and Toxicity
3.8.3 Risk Factors
3.9 Sorivudine
3.9.1 Drug Metabolism and Toxicity
3.9.2 Transporters and Toxicity
3.9.3 Risk Factors
3.10 Tacrine
3.10.1 Drug Metabolism and Toxicity
3.10.2 Transporters and Toxicity
3.10.3 Risk Factors
3.11 Terfenadine
3.11.1 Drug Metabolism and Toxicity
3.11.2 Transporter and Toxicity
3.11.3 Risk Factors
3.12 Troglitazone (Rezulin®)
3.12.1 Drug Metabolism and Toxicity
3.12.2 Transporter and Toxicity
3.12.3 Risk Factors
3.13 Trovafloxacin
3.13.1 Metabolism and Toxicity
3.13.2 Transporters and Toxicity
3.13.3 Risk Factors
3.14 Conclusions
References
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