Transporters and Drug-Metabolizing Enzymes in Drug Toxicity

TRANSPORTERS AND DRUG-METABOLIZING ENZYMES IN DRUG TOXICITY
 
Explore up-to-date coverage on the interaction between drug metabolism enzymes, transporters, and drug toxicity with this leading resources
 
Transporters and Drug-Metabolizing Enzymes in Drug Toxicity delivers a comprehensive and updated review of the relationship between drug metabolism, transporters, and toxicity, providing insights into a major challenge in drug development - accurate assessment of human drug toxicity. Combining two disciplines frequently considered independently of one another, the book combines drug metabolism and toxicology with a focus on the role of biotransformation on drug toxicity and as a major factor for species and individual differences.
 
Mechanism and species differences in drug metabolizing enzymes and transporters are discussed, as are the methods used to investigate the role of drug metabolizing enzymes and transporters in drug toxicity.
 
Finally, the distinguished authors describe promising new experimental approaches to accurately assessing human drug toxicity via the consideration of human-specific drug metabolism in toxicity assays. In addition to topics as diverse as extended clearance models, experimental approaches for the estimation of DILI potential of drug candidates and roles of transporters in renal drug toxicity, readers will also enjoy the inclusion of such subjects as:
* A thorough overview of and introduction to drug metabolism and transporters and drug toxicity
* An exploration of drug metabolism enzymes and transporter activities as risk factors of marketed drugs associated with drug-induced fatalities
* A discussion of human-based in vitro experimental models for the evaluation of metabolism-dependent drug toxicity
* A treatment of mechanism-based experimental models for the evaluation of BSEP inhibition and DILI
* An examination of transporters and cochlea toxicity
 
Perfect for scientists, students, and practitioners with interests in metabolism, toxicology, and drug development in the pharmaceutical industry, Transporters and Drug-Metabolizing Enzymes in Drug Toxicity will also earn a place in the libraries of medicinal chemists, pharmacologists, biochemists, toxicologists, and regulators in the pharmaceutical and health industries.

List of contents

Preface xix
 
List of Contributors xxi
 
Part I Overview 1
 
1 Overview: Drug Metabolism, Transporter-Mediated Uptake and Efflux, and Drug Toxicity 3
Albert P. Li
 
1.1 Drug Toxicity as a Challenge in Drug Development 3
 
1.2 Fate of an Orally Administered Drug 4
 
1.3 The Multiple Determinant Hypothesis for Idiosyncratic Drug Toxicity 5
 
1.4 Concluding Remarks 7
 
1.4.1 A Comprehensive Approach to Safety Evaluation in Drug Development 7
 
1.4.2 The Dose Makes the Poison - Paracelsus Updated 8
 
References 8
 
2 Transporter, Drug Metabolism, and Drug-Induced Liver Injury in Marketed Drugs 11
Minjun Chen, Kristin Ashby, and Yue Wu
 
2.1 Introduction 11
 
2.2 Hepatic Metabolism 12
 
2.2.1 Phase I Metabolism 12
 
2.2.2 Phase II Metabolism 14
 
2.3 Reactive Metabolite Formation and Assessment 14
 
2.3.1 Metabolism and Reactive Metabolites 15
 
2.3.2 Dose and Reactive Mtabolites 16
 
2.3.3 Structural Alerts for Avoiding Reactive Metabolites 16
 
2.3.4 Experimental Approaches for Assessing Reactive Metabolites 18
 
2.3.4.1 Covalent Binding Assay 18
 
2.3.4.2 Electrophile Trapping Experiments 18
 
2.3.4.3 Time Dependent Inactivation of CYP450 Enzymes 19
 
2.4 Hepatic Transporters 20
 
2.5 Genetic Variants and Their Impact for Pharmacokinetic Behavior and Safety 24
 
2.5.1 CYP3A424
 
2.5.2 CYP3A526
 
2.5.3 CYP2D626
 
2.5.4 CYP2C927
 
2.5.5 CYP2C1927
 
2.5.6 CYP2B628
 
2.5.7 UGT1A128
 
2.5.8 NAT2 28
 
2.5.9 Hepatic Transporters 29
 
2.6 Summary 29
 
Acknowledgment 30
 
Disclaimer 30
 
References 30
 
3 Drug-Metabolism Enzymes and Transporter Activities as Risk Factors of Selected Marketed Drugs Associated with Drug-Induced Fatalities 41
Albert P. Li
 
3.1 Introduction 41
 
3.2 Acetaminophen 41
 
3.2.1 Drug Metabolism and Toxicity 42
 
3.2.2 Transporters and Toxicity 42
 
3.2.3 Risk Factors 43
 
3.3 Cerivastatin 43
 
3.3.1 Drug Metabolism and Toxicity 43
 
3.3.2 Transporter and Toxicity 44
 
3.3.3 Risk Factors 44
 
3.4 Felbamate 45
 
3.4.1 Drug Metabolism and Toxicity 45
 
3.4.2 Transporters and Toxicity 46
 
3.4.3 Risk Factors 46
 
3.5 Flucloxacillin 46
 
3.5.1 Drug Metabolism and Toxicity 46
 
3.5.2 Transporters and Toxicity 47
 
3.5.3 Risk Factors 47
 
3.6 Nefazodone 47
 
3.6.1 Drug Metabolism and Toxicity 48
 
3.6.2 Transporters and Toxicity 48
 
3.6.3 Risk Factors 48
 
3.7 Obeticholic Acid 49
 
3.7.1 Drug Metabolism and Toxicity 49
 
3.7.2 Transporters and Toxicity 50
 
3.7.3 Risk Factors 50
 
3.8 Sitaxentan 50
 
3.8.1 Drug Metabolism and Toxicity 51
 
3.8.2 Transporters and Toxicity 51
 
3.8.3 Risk Factors 51
 
3.9 Sorivudine 52
 
3.9.1 Drug Metabolism and Toxicity 52
 
3.9.2 Transporters and Toxicity 52
 
3.9.3 Risk Factors 52
 
3.10 Tacrine 52
 
3.10.1 Drug Metabolism and Toxicity 54
 
3.10.2 Transporters and Toxicity 54
 
3.10.3 Risk Factors 54
 
3.11 Terfenadine 55
 
3.11.1 Drug Metabolism and Toxicity 55
 
3.11.2 Transporter and Toxicity 56
 
3.11.3 Risk Factors 56
 
3.12 Troglitazone (Rezulin(r)) 56
 
3.12.1 Drug Metabolism and Toxicity 57
 
3.12.2 Transporter and Toxicity 57
 
3.12.3 Risk Factors 58
 

About the author

Albert P. Li, PhD, is President and CEO of In Vitro ADMET Laboratories. Dr. Li was previously Senior Fellow of Monsanto Company and Research Professor of St. Louis University Medical School. He is Chair of the Scientific Advisory Board for the Institute for Scientific Communication and the editor/co-editor of several books for Wiley, including Drug-Drug Interactions in Pharmaceutical Development (2007) and Enzyme Inhibition in Drug Discovery and Development (2009). He currently has over 180 publications in peer-reviewed journals and frequently serves as chair and speaker in national and international conferences and symposia on drug metabolism and toxicology.<

Summary

This book provides a comprehensive and up-to-date coverage of the relationship between drug metabolism enzymes and transporters on drug toxicity.

Product details

• Authors: Li, Albert P Li, Albert P. Li, Ap Li, Li Albert P.
• Publisher: Wiley, John and Sons Ltd
• Languages: English
• Product format: Hardback
• Released: 31.12.2018
• EAN: 9781119170846
• ISBN: 978-1-119-17084-6
• No. of pages: 528
• Subjects: Natural sciences, medicine, IT, technology > Chemistry > Miscellaneous; Chemie, Toxikologie, Pharmakologie, Enzyme, Life Sciences, Biowissenschaften, chemistry, Zell- u. Molekularbiologie, Cell & Molecular Biology, Toxicology