Reactive Drug Metabolites

InhaltsangabePREFACE 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 MechanismBased Inactivation of Other DrugMetabolizing 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 WellKnown Examples of Bioactivation of Compounds Present in Herbal Remedies WellKnown 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

Amit Kalgutkar received his PhD in Organic Chemistry from Virginia Polytechnic Institute (USA) and conducted a post-doctoral fellowship at the Department of Biochemistry, Vanderbilt University School of Medicine. He joined Pfi zer in 1999, where he is currently a Research Fellow in the Drug Metabolism Group (Groton Laboratories). In addition, Dr. Kalgutkar is an adjunct Professor in the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island. Deepak Dalvie received his PhD 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 Pfi zer in 1992, where he is currently a Research Fellow in the Pharmacokinetics, Dynamics and Metabolism Department at Pfi zer'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 PhD in biochemistry from Brandeis University and was a post-doctoral fellow at the New York State Department of Health Research Labs. He joined Pfi zer 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. Dennis Smith worked in the pharmaceutical industry for more than 30 years since gaining his PhD from the University of Manchester (UK). For 20 years he was at Pfi zer 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. Now retired, he is still active in an academic (Visiting Professor, University of Liverpool; Honary Professor, University of Capetown) and in an advisory capacity. He has authored over 130 publications including three books.

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