Reactive Drug Metabolites

Hugo Kubinyi 지음

Wiley-VCH 2012년 09월 06일 출간

작품소개

책소개

Closing a gap in the scientifi c literature, this first comprehensive introduction to the topic is based on current best practice in one of the largestpharmaceutical companies worldwide. The first chapters trace the development of our understanding of drug metabolite toxicity, covering basic concepts and techniques in the process, while the second part details chemical toxicophores that are prone to reactive metabolite formation. This section also reviews the various drug-metabolizing enzymes that can participate in catalyzing reactive metabolite formation, including a discussion of the structure-toxicity relationships for drugs. Two chapters are dedicated to the currently hot topics of herbal constituents and IADRs.The next part covers current strategies and approaches to evaluate the reactive metabolite potential of new drug candidates, both by predictiveand by bioanalytical methods. There then follows an in-depth analysis of the toxicological potential of the top 200 prescription drugs, illustratingthe power and the limits of the toxicophore concept, backed by numerous case studies. Finally, a risk-benefi t approach to managing the toxicity risk of reactive metabolite-prone drugs is presented.Since the authors carefully develop the knowledge needed, from fundamental considerations to current industry standards, no degree in pharmacology is required to read this book, making it perfect for medicinal chemists without in-depth pharmacology training.

목차

Preface XIIIA Personal Foreword XV1 Origin and Historical Perspective on Reactive Metabolites 1Abbreviations 11.1 Mutagenesis and Carcinogenesis 11.2 Detection of Reactive Metabolites 31.3 Induction and Inhibition: Early Probes for Reactive Metabolites and Hepatotoxicants 41.4 Covalent Binding and Oxidative Stress: Possible Mechanisms of Reactive Metabolite Cytotoxicity 51.5 Activation and Deactivation: Intoxication and Detoxification 61.6 Genetic Influences on Reactive Metabolite Formation 61.7 Halothane: the Role of Reactive Metabolites in Immune-Mediated Toxicity 71.8 Formation of Reactive Metabolites, Amount Formed, and Removal of Liability 81.9 Antibodies: Possible Clues but Inconclusive 81.10 Parent Drug and Not Reactive Metabolites, Complications in Immune-Mediated Toxicity 91.11 Reversible Pharmacology Should not be Ignored as a Primary Cause of Side Effects 101.12 Conclusions: Key Points in the Introduction 10References 112 Role of Reactive Metabolites in Genotoxicity 13Abbreviations 132.1 Introduction 132.2 Carcinogenicity of Aromatic and Heteroaromatic Amines 132.3 Carcinogenicity of Nitrosamines 172.4 Carcinogenicity of Quinones and Related Compounds 192.5 Carcinogenicity of Furan 232.6 Carcinogenicity of Vinyl Halides 262.7 Carcinogenicity of Ethyl Carbamate 262.8 Carcinogenicity of Dihaloalkanes 282.9 Assays to Detect Metabolism-Dependent Genotoxicity in Drug Discovery 282.10 Case Studies in Eliminating Metabolism-Based Mutagenicity in Drug Discovery Programs 29References 363 Bioactivation and Inactivation of Cytochrome P450 and Other Drug-Metabolizing Enzymes 43Abbreviations 433.1 Introduction 433.2 Pharmacokinetic and Enzyme Kinetic Principles Underlying Mechanism-Based Inactivation and Drug&n-Dr

작가정보

저자(글) Hugo Kubinyi

저자 :

저자 :

저자 :

저자 :

저자 :
저자 :
저자 :
Amit Kalgutkar received his academic degrees from the University of Bombay (India) and from Virginia Polytechnic Institute (USA). Joining Pfizer in 1999, he is currently a Research Fellow in the Pharmacokinetics, Dynamics and Metabolism Department at Pfizer (Groton Laboratories). He is also an adjunct faculty member in the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island. Deepak Dalvie received his Ph.D. in Medicinal Chemistry from State University at New York, Buffalo (USA) and was a post-doctoral fellow at the Department of Chemistry in University of Virginia and Virginia Polytechnic Institute (USA). He joined Pfizer in 1992, where he is currently a Research Fellow in the Pharmacokinetics, Dynamics and Metabolism Department at Pfizer's La Jolla site. In addition, Dr. Dalvie is an Associate Editor for Drug Metabolism and Disposition and on the editorial board of Xenobiotica. Scott Obach received his Ph.D. in biochemistry from Brandeis University and was a post-doctoral fellow at the New York State Department of Health Research Labs. He joined Pfizer in 1992, where he is currently a Senior Research Fellow in the Pharmacokinetics, Dynamics, and Drug Metabolism Department at Pfizer in Groton (USA). In addition, Dr. Obach is on the editorial boards of Drug Metabolism and Disposition, Chemical Research in Toxicology, Xenobiotica, and Drug Metabolism and Pharmacokinetics. He is an author or coauthor on over 120 research publications. Dennis Smith has worked in the pharmaceutical industry for 32 years after gaining his Ph.D from the University of Manchester (UK). For 20 years he was at Pfizer Global Research and Development, Sandwich where he was Vice President-Pharmacokinetics, Dynamics and Metabolism. During this time he has helped in the Discovery and Development of eight marketed NCEs. He has authored over 130 publications including three books.