Reactive Drug Metabolites
(Sprache: Englisch)
This first comprehensive introduction to the topic discusses the current best practice to manage toxicity risks in new drugs, including an in-depth analysis of the toxicological potential of the top 200 prescription drugs.
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Produktinformationen zu „Reactive Drug Metabolites “
This first comprehensive introduction to the topic discusses the current best practice to manage toxicity risks in new drugs, including an in-depth analysis of the toxicological potential of the top 200 prescription drugs.
Klappentext zu „Reactive Drug Metabolites “
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.
Inhaltsverzeichnis zu „Reactive Drug Metabolites “
PREFACEORIGIN AND HISTORICAL PERSPECTIVE ON REACTIVE METABOLITESMutagenesis and CarcinogenesisDetection of Reactive MetabolitesInduction and Inhibition: Early Probes for Reactive Metabolites and HepatotoxicantsCovalent Binding and Oxidative Stress: Possible Mechanisms of Reactive Metabolite CytotoxicityActivation and Deactivation: Intoxication and DetoxificationGenetic Influences on Reactive Metabolite FormationHalothane: the Role of Reactive Metabolites in Immune-Mediated ToxicityFormation of Reactive Metabolites, Amount Formed, and Removal of LiabilityAntibodies: Possible Clues but InconclusiveParent Drug and Not Reactive Metabolites, Complications in Immune-Mediated ToxicityReversible Pharmacology Should not be ignored as a Primary Cause of Side EffectsConclusions: Key Points in the IntroductionROLE OF REACTIVE METABOLITES IN GENOTOXICITYIntroductionCarcinogenicity of Aromatic and Heteroaromatic AminesCarcinogenicity of NitrosaminesCarcinogenicity of Quinones and Related CompoundsCarcinogenicity of FuranCarcinogenicity of Vinyl HalidesCarcinogenicity of Ethyl CarbamateCarcinogenicity of DihaloalkanesAssays to Detect Metabolism-Dependent Genotoxicity in Drug DiscoveryCase Studies in Eliminating Metabolism-Based Mutagenicity in Drug Discovery ProgramsBIOACTIVATION AND INACTIVATION OF CYTOCHROME P450 AND OTHER DRUG-METABOLIZING ENZYMESIntroductionPharmacokinetic and Enzyme Kinetic Principles Underlying Mechanism-Based Inactivation and Drug - Drug InteractionsMechanisms of Inactivation of Cytochrome P450 EnzymesExamples of Drugs and Other Compounds that are Mechanism-Based Inactivators of Cytochrome P450 EnzymesMechanism-Based Inactivation of Other Drug-Metabolizing EnzymesConcluding RemarksROLE OF REACTIVE METABOLITES IN DRUG-INDUCED TOXICITY - THE TALE OF ACETAMINOPHEN, HALOTHANE, HYDRALAZINE, AND TIENILIC ACIDIntroductionAcetaminophenHalothaneHydralazineTienilic AcidPATHWAYS OF REACTIVE METABOLITE FORMATION WITH TOXICOPHORES/-STRUCTURAL
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ALERTSIntroductionIntrinsically Reactive ToxicophoresToxicophores that Require Bioactivation to Reactive MetabolitesConcluding RemarksINTRINSICALLY ELECTROPHILIC COMPOUNDS AS A LIABILITY IN DRUG DISCOVERYIntroductionIntrinsic Electrophilicity of b-Lactam Antibiotics as a Causative Factor in ToxicityIntrinsically Electrophilic Compounds in Drug DiscoverySerendipitous Identification of Intrinsically Electrophilic Compounds in Drug DiscoveryROLE OF REACTIVE METABOLITES IN PHARMACOLOGICAL ACTIONIntroductionDrugs Activated Nonenzymatically and by Oxidative MetabolismBioreductive Activation of DrugsConcluding RemarksRETROSPECTIVE ANALYSIS OF STRUCTURE - TOXICITY RELATIONSHIPS OF DRUGSIntroductionIrreversible Secondary PharmacologyPrimary Pharmacology and Irreversible Secondary PharmacologyPrimary or Secondary Pharmacology and Reactive Metabolites: the Possibility for False Structure - Toxicity RelationshipsMultifactorial Mechanisms as Causes of ToxicityClear Correlation between Protein Target and Reactive MetabolitesConclusion - Validation of Reactive Metabolites as Causes of ToxicityBIOACTIVATION AND NATURAL PRODUCTSIntroductionWell-Known Examples of Bioactivation of Compounds Present in Herbal RemediesWell-Known Examples of Bioactivation of Compounds Present inFoodsSummaryEXPERIMENTAL APPROACHES TO REACTIVE METABOLITE DETECTIONIntroductionIdentification of Structural Alerts and avoiding them in Drug DesignAssays for the Detection of Reactive MetabolitesOther Studies that can Show the Existence of Reactive MetabolitesConclusionCASE STUDIES ON ELIMINATING/REDUCING REACTIVE METABOLITE FORMATION IN DRUG DISCOVERYMedicinal Chemistry Tactics to Eliminate Reactive Metabolite FormationEliminating Reactive Metabolite Formation on Heterocyclic Ring SystemsMedicinal Chemistry Strategies to Mitigate Bioactivation of Electron-Rich Aromatic RingsMedicinal Chemistry Strategies to Mitigate Bioactivation on a Piperazine Ring SystemConcluding RemarksSTRUCTURAL ALERT AND REACTIVE METABOLITE ANALYSIS FOR THE TOP 200 DRUGS IN THE US MARKET BY PRESCRIPTIONIntroductionStructural Alert and Reactive Metabolite Analyses for the Top 20 Most Prescribed Drugs in the United States for the Year 2009Insights into the Excellent Safety Records for Reactive Metabolite - Positive Blockbuster DrugsStructural Alert and Reactive Metabolite Analyses for the Remaining 180 Most Prescribed DrugsStructure Toxicity TrendsMITIGATING TOXICITY RISKS WITH AFFINITY LABELING DRUG CANDIDATESIntroductionDesigning Covalent InhibitorsOptimization of Chemical Reactivity of the Warhead MoietyConcluding RemarksDEALING WITH REACTIVE METABOLITE - POSITIVE COMPOUNDS IN DRUG DISCOVERYIntroductionAvoiding the Use of Structural Alerts in Drug DesignStructural Alert and Reactive Metabolite FormationShould Reactive Metabolite - Positive Compounds be nominated as Drug Candidates?The Multifactorial Nature of IADRsConcluding RemarksMANAGING IADRS ' A RISK' BENEFIT ANALYSISRisk - Benefit AnalysisHow common is Clinical Drug Toxicity?Rules and Laws of Drug ToxicityDifficulties in Defining Cause and Black Box WarningsLabeling Changes, Contraindications, and Warnings: the Effectiveness of Side Effect MonitoringAllele Association with Hypersensitivity Induced by Abacavir: Toward a Biomarker for ToxicityMore Questions than Answers: Benefit Risk for ADRsINDEX
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Autoren-Porträt von Amit S. Kalgutkar, Deepak Dalvie, R. Scott Obach, Dennis A. Smith
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 inan academic (Visiting Professor, University of Liverpool; Honary Professor, University of Capetown) and in an
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advisory capacity. He has authored over 130 publications including three books.
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Bibliographische Angaben
- Autoren: Amit S. Kalgutkar , Deepak Dalvie , R. Scott Obach , Dennis A. Smith
- 2012, XVI, 386 Seiten, 238 Schwarz-Weiss-Abbildungen, Masse: 17,8 x 25 cm, Gebunden, Englisch
- Verlag: Wiley-VCH
- ISBN-10: 3527330852
- ISBN-13: 9783527330850
- Erscheinungsdatum: 29.10.2012
Sprache:
Englisch
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