Transporters and Drug-Metabolizing Enzymes in Drug Toxicity. Albert P. Li

      

      Table of Contents

      1  Cover

      2  Title Page

      3  Copyright Page

      4  Preface

      5  List of Contributors

      6  Part I: Overview 1 Overview 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 References 2 Transporter, Drug Metabolism, and Drug‐Induced Liver Injury in Marketed Drugs 2.1 Introduction 2.2 Hepatic Metabolism 2.3 Reactive Metabolite Formation and Assessment 2.4 Hepatic Transporters 2.5 Genetic Variants and Their Impact for Pharmacokinetic Behavior and Safety 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 3.3 Cerivastatin 3.4 Felbamate 3.5 Flucloxacillin 3.6 Nefazodone 3.7 Obeticholic Acid 3.8 Sitaxentan 3.9 Sorivudine 3.10 Tacrine 3.11 Terfenadine 3.12 Troglitazone (Rezulin®) 3.13 Trovafloxacin 3.14 Conclusions References

      7  Part II: Drug Metabolizing Enzymes and Drug Toxicity 4 Drug‐Metabolizing Enzymes and Drug Toxicity 4.1 Introduction 4.2 Drug‐Metabolism Enzymes Involved in Metabolic Activation and Detoxification 4.3 Cytochrome P450 Monooxygenase (CYP) 4.4 Non‐P450 Drug‐Metabolizing Enzymes 4.5 Conclusions References 5 Genetic Polymorphism of Drug‐Metabolizing Enzymes and Drug Transporters in Drug Toxicity 5.1 Introduction 5.2 Drug‐Induced Liver Injury 5.3 Drug‐Induced Skin Injury and Related Hypersensitivity Reactions 5.4 Statin‐Induced Myopathy 5.5 Conclusions References 6 Acyl Glucuronidation and Acyl‐CoA Formation Mechanisms Mediating the Bioactivation and Potential Toxicity of Carboxylic Acid‐containing Drugs 6.1 Introduction 6.2 Phase II Metabolism 6.3 Chemical Stability of Phase II Metabolites 6.4 Phase II Metabolite Chemical Reactivity 6.5 Phase II Metabolite‐Mediated Covalent Binding 6.6 Phase II Metabolite Prediction of Covalent Binding 6.7 Studies Directly Comparing Carboxylic Acid Drug Bioactivation by Acyl Glucuronidation and Acyl‐CoA Formation 6.8 Prediction of Drug‐Induced Liver Injury for Carboxylic Acid Drugs 6.9 Conclusions References 7 Liquid Chromatography‐Mass Spectrometry (LC‐MS) Quantification of Reactive Metabolites 7.1 Introduction 7.2 LC‐MS Methods Using GSH as a Trapping Reagent 7.3 Using Other Trapping Reagents 7.4 Identification and Characterization of Rearranged GSH Adducts 7.5 Strategies for Optimization