Reactive Drug Metabolites

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Beschreibung

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 largest pharmaceutical 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 predictive and by bioanalytical methods. There then follows an in-depth analysis of the toxicological potential of the top 200 prescription drugs, illustrating the 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.



Autorentext
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.

Inhalt
PREFACE

ORIGIN AND HISTORICAL PERSPECTIVE ON REACTIVE METABOLITES
Mutagenesis and Carcinogenesis
Detection of Reactive Metabolites
Induction and Inhibition: Early Probes for Reactive Metabolites and Hepatotoxicants
Covalent Binding and Oxidative Stress: Possible Mechanisms of Reactive Metabolite Cytotoxicity
Activation and Deactivation: Intoxication and Detoxification
Genetic Influences on Reactive Metabolite Formation
Halothane: the Role of Reactive Metabolites in Immune-Mediated Toxicity
Formation of Reactive Metabolites, Amount Formed, and Removal of Liability
Antibodies: Possible Clues but Inconclusive
Parent Drug and Not Reactive Metabolites, Complications in Immune-Mediated Toxicity
Reversible Pharmacology Should not be ignored as a Primary Cause of Side Effects
Conclusions: Key Points in the Introduction

ROLE OF REACTIVE METABOLITES IN GENOTOXICITY
Introduction
Carcinogenicity of Aromatic and Heteroaromatic Amines
Carcinogenicity of Nitrosamines
Carcinogenicity of Quinones and Related Compounds
Carcinogenicity of Furan
Carcinogenicity of Vinyl Halides
Carcinogenicity of Ethyl Carbamate
Carcinogenicity of Dihaloalkanes
Assays to Detect Metabolism-Dependent Genotoxicity in Drug Discovery
Case Studies in Eliminating Metabolism-Based Mutagenicity in Drug Discovery Programs

BIOACTIVATION AND INACTIVATION OF CYTOCHROME P450 AND OTHER DRUG-METABOLIZING ENZYMES
Introduction
Pharmacokinetic and Enzyme Kinetic Principles Underlying Mechanism-Based Inactivation and Drug -
Drug Interactions
Mechanisms of Inactivation of Cytochrome P450 Enzymes
Examples of Drugs and Other Compounds that are Mechanism-Based Inactivators of Cytochrome P450 Enzymes
Mechanism-Based Inactivation of Other Drug-Metabolizing Enzymes
Concluding Remarks

ROLE OF REACTIVE METABOLITES IN DRUG-INDUCED TOXICITY -
THE TALE OF ACETAMINOPHEN, HALOTHANE, HYDRALAZINE, AND TIENILIC ACID
Introduction
Acetaminophen
Halothane
Hydralazine
Tienilic Acid

PATHWAYS OF REACTIVE METABOLITE FORMATION WITH TOXICOPHORES/-STRUCTURAL ALERTS
Introduction
Intrinsically Reactive Toxicophores
Toxicophores that Require Bioactivation to Reactive Metabolites
Concluding Remarks

INTRINSICALLY ELECTROPHILIC COMPOUNDS AS A LIABILITY IN DRUG DISCOVERY
Introduction
Intrinsic Electrophilicity of b-Lactam Antibiotics as a Causative Factor in Toxicity
Intrinsically Electrophilic Compounds in Drug Discovery
Serendipitous Identification of Intrinsically Electrophilic Compounds in Drug Discovery

ROLE OF REACTIVE METABOLITES IN PHARMACOLOGICAL ACTION
Introduction
Drugs Activated Nonenzymatically and by Oxidative Metabolism
Bioreductive Activation of Drugs
Concluding Remarks

RETROSPECTIVE ANALYSIS OF STRUCTURE -
TOXICITY RELATIONSHIPS OF DRUGS
Introduction
Irreversible Secondary Pharmacology
Primary Pharmacology and Irreversible Secondary Pharmacology
Primary or Secondary Pharmacology and Reactive Metabolites: the Possibility for False Structure -
Toxicity Relationships
Multifactorial Mechanisms as Causes of Toxicity
Clear Correlation between Protein Target and Reactive Metabolites
Conclusion -
Validation of Reactive Metabolites as Causes of Toxicity

BIOACTIVATION AND NATURAL PRODUCTS
Introduction
Well-Known Examples of Bioactivation of Compounds Present in Herbal Remedies
Well-Known Examples of Bioactivation of Compounds Present inFoods
Summary

EXPERIMENTAL APPROACHES TO REACTIVE METABOLITE DETECTION
Introduction
Identification of Structural Alerts and avoiding them in Drug Design
Assays for the Detection of Reactive Metabolites
Other Studies that can Show the Existence of Reactive Metabolites
Conclusion

CASE STUDIES ON ELIMINATING/REDUCING REACTIVE METABOLITE FORMATION IN DRUG DISCOVERY
Medicinal Chemistry Tactics to Eliminate Reactive Metabolite Formation
Eliminating Reactive Metabolite Formation on Heterocyclic Ring Systems
Medicinal Chemistry Strategies to Mitigate Bioactivation of Electron-Rich Aromatic Rings
Medicinal Chemistry Strategies to Mitigate Bioactivation on a Piperazine Ring System
Concluding Remarks

STRUCTURAL ALERT AND R...

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Produktinformationen

Titel
Reactive Drug Metabolites
Autor
Editor
EAN
9783527655779
ISBN
978-3-527-65577-9
Format
E-Book (pdf)
Hersteller
Wiley-VCH
Herausgeber
Wiley-Vch
Genre
Medizin
Veröffentlichung
04.09.2012
Digitaler Kopierschutz
Adobe-DRM
Dateigrösse
8.47 MB
Anzahl Seiten
402
Jahr
2012
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