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Reactive Drug Metabolites - Amit S. Kalgutkar
Vergriffenes Buch, derzeit bei uns nicht verfügbar.
(*)
Amit S. Kalgutkar:
Reactive Drug Metabolites - neues Buch

2009, ISBN: 9783527655779

ID: 9783527655779

InhaltsangabePreface 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&ndash Drug Interactions 443.2.1 Enzyme Kinetic Principles of Mechanism-Based Inactivation 443.2.2 Pharmacokinetic Principles Underlying DDIs Caused by Mechanism-Based Inactivation 463.3 Mechanisms of Inactivation of Cytochrome P450 Enzymes 473.3.1 Quasi-Irreversible Inactivation 473.3.2 Heme Adducts 483.3.3 Protein Adducts 493.4 Examples of Drugs and Other Compounds that are Mechanism-Based Inactivators of Cytochrome P450 Enzymes 493.4.1 Amines 493.4.2 Methylenedioxyphenyl Compounds 513.4.3 Quinones, Quinone Imines, and Quinone Methides 523.4.4 Thiophenes 533.4.5 Furans 553.4.6 Alkynes 563.4.7 2-Alkylimidazoles 573.4.8 Other Noteworthy Cytochrome P450 Inactivators 583.5 Mechanism-Based Inactivation of Other Drug-Metabolizing Enzymes 603.5.1 Aldehyde Oxidase 603.5.2 Monoamine Oxidases 613.6 Concluding Remarks 64References 654 Role of Reactive Metabolites in Drug-Induced Toxicity &ndash The Tale of Acetaminophen, Halothane, Hydralazine, and Tienilic Acid 71Abbreviations 714.1 Introduction 714.2 Acetaminophen 714.2.1 Metabolism of Acetaminophen 724.2.2 Metabolic Activation of Acetaminophen 73&l 5.3.5.4 3-Alkyl Pyrrole and 3-Alkylindole Derivatives 1125.3.5.5 1,3-Benzdioxole (Methylenedioxyphenyl) Motif 1155.3.6 Terminal Alkenes and Alkynes 1175.4 Concluding Remarks 121References 1216 Intrinsically Electrophilic Compounds as a Liability in Drug Discovery 131Abbreviations 1316.1 Introduction 1316.2 Intrinsic Electrophilicity of b-Lactam Antibiotics as a Causative Factor in Toxicity 1316.3 Intrinsically Electrophilic Compounds in Drug Discovery 1336.3.1 Linking Innate Electrophilicity with Drug Toxicity 1356.4 Serendipitous Identification of Intrinsically Electrophilic Compounds in Drug Discovery 136References 1417 Role of Reactive Metabolites in Pharmacological Action 145Abbreviations 1457.1 Introduction 1457.2 Drugs Activated Nonenzymatically and by Oxidative Metabolism 1457.2.1 Proton Pump Inhibitors 1457.2.2 Nitrosoureas 1477.2.3 Imidazotriazenes 1487.2.4 Thienotetrahydropyridines 1507.2.5 Oxazaphosphorines 1527.2.6 N,N,N0,N0,N0,N0-Hexamethylmelamine 1537.3 Bioreductive Activation of Drugs 1537.3.1 Bioreduction to Radical Intermediates 1577.3.1.1 Tirapazamine 1577.3.1.2 Anthracyclines 1577.3.1.3 Enediynes 1587.3.1.4 Artemisinin Derivatives 1667.3.2 Bioreductive Activation to Electrophilic Intermediates 1687.3.2.1 Mitomycins 1687.3.2.2 Aziridinylbenzoquinones 1707.3.2.3 Bioreductive Activation of Anthracyclines to Alkylating Species 1737.3.2.4 Bioreductive Activation of Nitroaromatic Compounds 1747.4 Concluding Remarks 175References 1768 Retrospective Analysis of Structure&ndash Toxicity Relationships of Drugs 185Abbreviations 1858.1 Introduction 1858.2 Irreversible Secondary Pharmacology 1898.2.1 Common Structural Features: Carboxylic Acids 1898.3 Primary Pharmacology and Irreversible Secondary Pharmacology 1918.4 Primary or Secondary Pharmacology and Reactive Metabolites: the Possibility for False Structure&ndash Toxicity Relationships 1928.5 Multifactorial Mechanisms as Causes of Toxicity 1968.6 Clear Correlation between Protein Target and Reactive Metabolites 1978.7 Conclusion &ndash Validation of Reactive Metabolites as Causes of Toxicity 198References 2009 Bioactivation and Natural Products 203Abbreviations 2039.1 Introduction 2039.2 Well-Known Examples of Bioactivation of Compounds Present in Herbal Remedies 2059.2.1 Germander and Teucrin A 2059.2.2 Pennyroyal Oil and Menthofuran 2079.2.3 Aristolochia and Aristolochic Acid 2089.2.4 Comfrey, Coltsfoot, and Pyrrolizidine Alkaloids 2109.3 Well-Known Examples of Bioactivation of Compounds Present in Foods 2129.3.1 Cycasin 2129.3.2 Aflatoxin 2149.3.3 3-Methylindole 2169.3.4 Polycyclic Azaheterocyclic Compounds in Cooked Meats 2169.3.5 Nitrosamines 2199.4 Summary 220References 22010 Experimental Approaches to Reactive Metabolite Detection 225A 11.1 Medicinal Chemistry Tactics to Eliminate Reactive Metabolite Formation 24111.2 Eliminating Reactive Metabolite Formation on Heterocyclic Ring Systems 24211.2.1 Mechanism(s) of Thiazole Ring Bioactivation and Rational Chemistry Approaches to Abolish Reactive Metabolite Formation 24211.2.2 Mechanism(s) of Isothiazole Ring Bioactivation and Rational Chemistry Approaches to Abolish Reactive Metabolite Formation 24911.3 Medicinal Chemistry Strategies to Mitigate Bioactivation of Electron-Rich Aromatic Rings 25111.4 Medicinal Chemistry Strategies to Mitigate Bioactivation on a Piperazine Ring System 25611.5 4-Fluorofelbamate as a Potentially Safer Alternative to Felbamate 25811.6 Concluding Remarks 263References 26312 Structural Alert and Reactive Metabolite Analysis for the Top 200 Drugs in the US Market by Prescription 269Abbreviations 26912.1 Introduction 26912.2 Structural Alert and Reactive Metabolite Analyses for the Top 20 Most Prescribed Drugs in the United States for the Year 2009 27012.2.1 Daily Dose Trends 27012.2.2 Presence of Structural Alerts 27012.2.3 Evidence for Metabolic Activation to Reactive Metabolites 27512.3 Insights Into the Excellent Safety Records for Reactive Metabolite&ndash Positive Blockbuster Drugs 28012.4 Structural Alert and Reactive Metabolite Analyses for the Remaining 180 Most Prescribed Drugs 28212.4.1 Structural Alert and/or Reactive Metabolite &ldquo False Positives&rdquo 28912.5 Structure Toxicity Trends 30212.5.1 Meloxicam versus Sudoxicam 304 Reactive Drug Metabolites: InhaltsangabePreface 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&ndash Drug Interactions 443.2.1 Enzyme Kinetic Principles of Mechanism-Based Inactivation 443.2.2 Pharmacokinetic Principles Underlying DDIs Caused by Mechanism-Based Inactivation 463.3 Mechanisms of Inactivation of Cytochrome P450 Enzymes 473.3.1 Quasi-Irreversible Inactivation 473.3.2 Heme Adducts 483.3.3 Protein Adducts 493.4 Examples of Drugs and Other Compounds that are Mechanism-Based Inactivators of Cytochrome P450 Enzymes 493.4.1 Amines 493.4.2 Methylenedioxyphenyl Compounds 513.4.3 Quinones, Quinone Imines, and Quinone Methides 523.4.4 Thiophenes 533.4.5 Furans 553.4.6 Alkynes 563.4.7 2-Alkylimidazoles 573.4.8 Other Noteworthy Cytochrome P450 Inactivators 583.5 Mechanism-Based Inactivation of Other Drug-Metabolizing Enzymes 603.5.1 Aldehyde Oxidase 603.5.2 Monoamine Oxidases 613.6 Concluding Remarks 64References 654 Role of Reactive Metabolites in Drug-Induced Toxicity &ndash The Tale of Acetaminophen, Halothane, Hydralazine, and Tienilic Acid 71Abbreviations 714.1 Introduction 714.2 Acetaminophen 714.2.1 Metabolism of Acetaminophen 724.2.2 Metabolic Activation of Acetaminophen 73&l 5.3.5.4 3-Alkyl Pyrrole and 3-Alkylindole Derivatives 1125.3.5.5 1,3-Benzdioxole (Methylenedioxyphenyl) Motif 1155.3.6 Terminal Alkenes and Alkynes 1175.4 Concluding Remarks 121References 1216 Intrinsically Electrophilic Compounds as a Liability in Drug Discovery 131Abbreviations 1316.1 Introduction 1316.2 Intrinsic Electrophilicity of b-Lactam Antibiotics as a Causative Factor in Toxicity 1316.3 Intrinsically Electrophilic Compounds in Drug Discovery 1336.3.1 Linking Innate Electrophilicity with Drug Toxicity 1356.4 Serendipitous Identification of Intrinsically Electrophilic Compounds in Drug Discovery 136References 1417 Role of Reactive Metabolites in Pharmacological Action 145Abbreviations 1457.1 Introduction 1457.2 Drugs Activated Nonenzymatically and by Oxidative Metabolism 1457.2.1 Proton Pump Inhibitors 1457.2.2 Nitrosoureas 1477.2.3 Imidazotriazenes 1487.2.4 Thienotetrahydropyridines 1507.2.5 Oxazaphosphorines 1527.2.6 N,N,N0,N0,N0,N0-Hexamethylmelamine 1537.3 Bioreductive Activation of Drugs 1537.3.1 Bioreduction to Radical Intermediates 1577.3.1.1 Tirapazamine 1577.3.1.2 Anthracyclines 1577.3.1.3 Enediynes 1587.3.1.4 Artemisinin Derivatives 1667.3.2 Bioreductive Activation to Electrophilic Intermediates 1687.3.2.1 Mitomycins 1687.3.2.2 Aziridinylbenzoquinones 1707.3.2.3 Bioreductive Activation of Anthracyclines to Alkylating Species 1737.3.2.4 Bioreductive Activation of Nitroaromatic Compounds 1747.4 Concluding Remarks 175References 1768 Retrospective Analysis of Structure&ndash Toxicity Relationships of Drugs 185Abbreviations 1858.1 Introduction 1858.2 Irreversible Secondary Pharmacology 1898.2.1 Common Structural Features: Carboxylic Acids 1898.3 Primary Pharmacology and Irreversible Secondary Pharmacology 1918.4 Primary or Secondary Pharmacology and Reactive Metabolites: the Possibility for False Structure&ndash Toxicity Relationships 1928.5 Multifactorial Mechanisms as Causes of Toxicity 1968.6 Clear Correlation between Protein Target and Reactive Metabolites 1978.7 Conclusion &ndash Validation of Reactive Metabolites as Causes of Toxicity 198References 2009 Bioactivation and Natural Products 203Abbreviations 2039.1 Introduction 2039.2 Well-Known Examples of Bioactivation of Compounds Present in Herbal Remedies 2059.2.1 Germander and Teucrin A 2059.2.2 Pennyroyal Oil and Menthofuran 2079.2.3 Aristolochia and Aristolochic Acid 2089.2.4 Comfrey, Coltsfoot, and Pyrrolizidine Alkaloids 2109.3 Well-Known Examples of Bioactivation of Compounds Present in Foods 2129.3.1 Cycasin 2129.3.2 Aflatoxin 2149.3.3 3-Methylindole 2169.3.4 Polycyclic Azaheterocyclic Compounds in Cooked Meats 2169.3.5 Nitrosamines 2199.4 Summary 220References 22010 Experimental Approaches to Reactive Metabolite Detection 225A 11.1 Medicinal Chemistry Tactics to Eliminate Reactive Metabolite Formation 24111.2 Eliminating Reactive Metabolite Formation on Heterocyclic Ring Systems 24211.2.1 Mechanism(s) of Thiazole Ring Bioactivation and Rational Chemistry Approaches to Abolish Reactive Metabolite Formation 24211.2.2 Mechanism(s) of Isothiazole Ring Bioactivation and Rational Chemistry Approaches to Abolish Reactive Metabolite Formation 24911.3 Medicinal Chemistry Strategies to Mitigate Bioactivation of Electron-Rich Aromatic Rings 25111.4 Medicinal Chemistry Strategies to Mitigate Bioactivation on a Piperazine Ring System 25611.5 4-Fluorofelbamate as a Potentially Safer Alternative to Felbamate 25811.6 Concluding Remarks 263References 26312 Structural Alert and Reactive Metabolite Analysis for the Top 200 Drugs in the US Market by Prescription 269Abbreviations 26912.1 Introduction 26912.2 Structural Alert and Reactive Metabolite Analyses for the Top 20 Most Prescribed Drugs in the United States for the Year 2009 27012.2.1 Daily Dose Trends 27012.2.2 Presence of Structural Alerts 27012.2.3 Evidence for Metabolic Activation to Reactive Metabolites 27512.3 Insights Into the Excellent Safety Records for Reactive Metabolite&ndash Positive Blockbuster Drugs 28012.4 Structural Alert and Reactive Metabolite Analyses for the Remaining 180 Most Prescribed Drugs 28212.4.1 Structural Alert and/or Reactive Metabolite &ldquo False Positives&rdquo 28912.5 Structure Toxicity Trends 30212.5.1 Meloxicam versus Sudoxicam 304 Basic Pharmacology Chemie Chemistry Drug Discovery & Development Grundlagen der Pharmakologie Medical Science Medizin Toxicology Toxikologie Wirkstoffforschung Wirkstoffforschung u. -entwicklung, Wiley-VCH

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Reactive Drug Metabolites, Volume 55 - Adolf Schwab
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Adolf Schwab:
Reactive Drug Metabolites, Volume 55 - neues Buch

ISBN: 9783527655779

ID: 9783527655779

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.; PDF; Scientific, Technical and Medical > Pre-clinical medicine: basic sciences > Physiology > Metabolism, Springer Berlin Heidelberg

Neues Buch Hive.co.uk
No. 9783527655779. Versandkosten:Instock, Despatched same working day before 3pm, zzgl. Versandkosten.
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Reactive Drug Metabolites - Amit S. Kalgutkar;  Raimund Mannhold;  Hugo Kubinyi;  Deepak Dalvie;  Gerd Folkers;  R. Scott Obach;  Douglas A. Smith
Vergriffenes Buch, derzeit bei uns nicht verfügbar.
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Amit S. Kalgutkar; Raimund Mannhold; Hugo Kubinyi; Deepak Dalvie; Gerd Folkers; R. Scott Obach; Douglas A. Smith:
Reactive Drug Metabolites - Erstausgabe

2012, ISBN: 9783527655779

ID: 24995164

[ED: 1], Auflage, eBook Download (PDF), eBooks, [PU: Wiley-VCH]

Neues Buch Lehmanns.de
Versandkosten:Download sofort lieferbar, , Versandkostenfrei innerhalb der BRD (EUR 0.00)
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(*) Derzeit vergriffen bedeutet, dass dieser Titel momentan auf keiner der angeschlossenen Plattform verfügbar ist.
Reactive Drug Metabolites - Raimund Mannhold;  Amit S. Kalgutkar;  Hugo Kubinyi;  Deepak Dalvie;  Gerd Folkers;  R. Scott Obach;  Douglas A. Smith
Vergriffenes Buch, derzeit bei uns nicht verfügbar.
(*)
Raimund Mannhold; Amit S. Kalgutkar; Hugo Kubinyi; Deepak Dalvie; Gerd Folkers; R. Scott Obach; Douglas A. Smith:
Reactive Drug Metabolites - Erstausgabe

2012, ISBN: 9783527655779

ID: 24995164

[ED: 1], Auflage, eBook Download (PDF), eBooks, [PU: Wiley-VCH]

Neues Buch Lehmanns.de
Versandkosten:Download sofort lieferbar, , Versandkostenfrei innerhalb der BRD (EUR 0.00)
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(*) Derzeit vergriffen bedeutet, dass dieser Titel momentan auf keiner der angeschlossenen Plattform verfügbar ist.
Reactive Drug Metabolites - Amit S. Kalgutkar; Deepak Dalvie; R. Scott Obach; Dennis A. Smith
Vergriffenes Buch, derzeit bei uns nicht verfügbar.
(*)
Amit S. Kalgutkar; Deepak Dalvie; R. Scott Obach; Dennis A. Smith:
Reactive Drug Metabolites - Erstausgabe

2012, ISBN: 9783527655779

ID: 24995164

[ED: 1], 1. Auflage, eBook Download (PDF), eBooks, [PU: Wiley-VCH]

Neues Buch Lehmanns.de
Versandkosten:Download sofort lieferbar, , Versandkostenfrei innerhalb der BRD (EUR 0.00)
Details...
(*) Derzeit vergriffen bedeutet, dass dieser Titel momentan auf keiner der angeschlossenen Plattform verfügbar ist.