Reactive drug metabolites

Author(s)

• Kalgutkar, Amit S.

Bibliographic Information

Reactive drug metabolites

edited by Amit S. Kalgutkar ... [et al.]

（Methods and principles in medicinal chemistry / edited by R. Mannhold ... [et al.], 55）

Wiley-VCH, c2012

• : hbk

Note

Includes bibliographical references and index

Description and Table of Contents

Description

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.

Table of Contents

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 REACTIVE METABOLITE ANALYSIS FOR THE TOP 200 DRUGS IN THE US MARKET BY PRESCRIPTION Introduction Structural Alert and Reactive Metabolite Analyses for the Top 20 Most Prescribed Drugs in the United States for the Year 2009 Insights into the Excellent Safety Records for Reactive Metabolite - Positive Blockbuster Drugs Structural Alert and Reactive Metabolite Analyses for the Remaining 180 Most Prescribed Drugs Structure Toxicity Trends MITIGATING TOXICITY RISKS WITH AFFINITY LABELING DRUG CANDIDATES Introduction Designing Covalent Inhibitors Optimization of Chemical Reactivity of the Warhead Moiety Concluding Remarks DEALING WITH REACTIVE METABOLITE - POSITIVE COMPOUNDS IN DRUG DISCOVERY Introduction Avoiding the Use of Structural Alerts in Drug Design Structural Alert and Reactive Metabolite Formation Should Reactive Metabolite - Positive Compounds be nominated as Drug Candidates? The Multifactorial Nature of IADRs Concluding Remarks MANAGING IADRS ' A RISK' BENEFIT ANALYSIS Risk - Benefit Analysis How common is Clinical Drug Toxicity? Rules and Laws of Drug Toxicity Difficulties in Defining Cause and Black Box Warnings Labeling Changes, Contraindications, and Warnings: the Effectiveness of Side Effect Monitoring Allele Association with Hypersensitivity Induced by Abacavir: Toward a Biomarker for Toxicity More Questions than Answers: Benefit Risk for ADRs INDEX

by "Nielsen BookData"

Details

• NCID: BB14111215
• ISBN:
  • 9783527330850
• LCCN: 2012540819
• Country Code: gw
• Title Language Code: eng
• Text Language Code: eng
• Place of Publication: Weinheim
• Pages/Volumes: xvi, 385 p.
• Size: 25 cm
• Classification:
  • LCC : RA1238
  • NLM : W1
  • NLM : QV 600
  • DC23 : 615.1
• Subject Headings:
  • LCSH : Drugs -- Toxicology
  • MESH : Pharmaceutical Preparations -- adverse effects
  • MESH : Pharmaceutical Preparations -- metabolism
  • MESH : Drug Discovery
  • MESH : Drug Toxicity
• Parent Bibliography ID:
  • BA22871556