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Human Drug Metabolism, An Introduction, Second Editionprovides an accessible introduction to the subject and will beparticularly invaluable to those who already have someunderstanding of the life sciences. Completely revised and updatedthroughout, the new edition focuses only on essential chemicaldetail and includes patient case histories to illustrate theclinical consequences of changes in drug metabolism and its impacton patient welfare. After underlining the relationship between efficacy, toxicityand drug concentration, the book then considers how metabolizingsystems operate and how they…mehr

Produktbeschreibung
Human Drug Metabolism, An Introduction, Second Editionprovides an accessible introduction to the subject and will beparticularly invaluable to those who already have someunderstanding of the life sciences. Completely revised and updatedthroughout, the new edition focuses only on essential chemicaldetail and includes patient case histories to illustrate theclinical consequences of changes in drug metabolism and its impacton patient welfare. After underlining the relationship between efficacy, toxicityand drug concentration, the book then considers how metabolizingsystems operate and how they impact upon drug concentration, bothunder drug pressure and during inhibition. Factors affecting drugmetabolism, such as genetic polymorphisms, age and diet arediscussed and how metabolism can lead to toxicity is explained. Thebook concludes with the role of drug metabolism in the commercialdevelopment of therapeutic agents as well as the pharmacology ofsome illicit drugs.

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  • Produktdetails
  • Verlag: John Wiley & Sons
  • Seitenzahl: 360
  • Erscheinungstermin: 15.03.2010
  • Englisch
  • ISBN-13: 9780470689349
  • Artikelnr.: 37298627
Autorenporträt
Dr Michael D. Coleman, Presently senior lecturer in toxicology at Aston University. During his career, Dr. Coleman has worked at Liverpool University, Walter Reed Army Institute of Research in Washington D.C. and latterly Aston University. His substantial and original contribution to knowledge of the biochemical pharmacology and toxicology of antiparasitic drugs has been acknowledged in the award of the degree of Doctor of Science from Aston University in 2005.
Inhaltsangabe
Preface xv 1 Introduction 1 1.1 Therapeutic window 1 1.1.1 Introduction 1 1.1.2 Therapeutic index 3 1.1.3 Changes in dosage 3 1.1.4 Changes in rate of removal 4 1.2 Consequences of drug concentration changes 4 1.2.1 Drug failure 4 1.2.2 Drug toxicity 5 1.3 Clearance 6 1.3.1 Definitions 6 1.3.2 Clearance and elimination 7 1.3.3 Biotransformation prior to elimination 7 1.3.4 Intrinsic clearance 8 1.3.5 Clearance: influencing factors 8 1.4 First pass and drug extraction 9 1.4.1 First pass: gut contribution 9 1.4.2 First pass: hepatic contribution 10 1.4.3 First pass: low-extraction drugs 12 1.5 First pass and plasma drug levels 13 1.5.1 Introduction 13 1.5.2 Changes in clearance and plasma levels 14 1.6 Drug and xenobiotic metabolism 14 References 15 2 Drug Biotransformational Systems - Origins and Aims 17 2.1 Biotransforming enzymes 17 2.2 Threat of lipophilic hydrocarbons 18 2.3 Cell communication 19 2.3.1 Signal molecule evolution 19 2.3.2 Lipophilic hydrocarbons as signal molecules 20 2.4 False signal molecules: bioprotection 22 2.4.1 Endocrine disruption 22 2.4.2 Endocrine disruption: problems and solutions 23 2.4.3 Endocrine disruption: cosmetic and nutraceutical aspects 24 2.4.4 Endocrine disruption: microRNAs 25 2.5 Sites of biotransforming enzymes 26 2.6 Biotransformation and xenobiotic cell entry 27 2.6.1 Role of the liver 27 2.6.2 Drug and xenobiotic uptake: transporter systems 29 2.6.3 Hepatic and gut uptake (influx) transporter systems 30 2.6.4 Aims of biotransformation 31 2.6.5 Task of biotransformation 32 2.6.6 Phase's I-III of biotransformation: descriptions and classifications 33 2.6.7 Biotransformation and drug action 34 References 34 3 How Oxidative Systems Metabolise Substrates 37 3.1 Introduction 37 3.2 Capture of lipophilic molecules 37 3.3 Cytochrome P450s: nomenclature and methods of study 38 3.3.1 Classification 38 3.3.2 Methods of analysis 40 3.3.3 CYP key features and capabilities 42 3.4 CYPs: main and associated structures 44 3.4.1 General structure 44 3.4.2 Haem moiety 44 3.4.3 CYP flexible regions 45 3.4.4 Substrate binding in CYPs 46 3.4.5 Homotropic binding in CYPs 47 3.4.6 Heterotropic binding in CYPs 49 3.4.7 CYP complex formation 50 3.4.8 CYP REDOX partners (i): P450 oxidoreductase (POR) 50 3.4.9 CYP REDOX partners (ii): Cytochrome b5 52 3.5 Human CYP families and their regulation 54 3.5.1 CYP regulation: lifespan 55 3.5.2 CYP regulation: transcriptional 56 3.5.3 CYP regulation: post-translational 58 3.6 Main human CYP families 59 3.6.1 CYP1A series 59 3.6.2 CYP2 series 61 3.6.3 CYP3A series 69 3.7 Cytochrome P450 catalytic cycle 71 3.7.1 Substrate binding 72 3.7.2 Oxygen binding 72 3.7.3 Oxygen scission (splitting) 74 3.7.4 Insertion of oxygen into substrate 75 3.7.5 Release of product 75 3.7.6 Reductions 76 3.8 Flavin monooxygenases (FMOs) 76 3.8.1 Introduction 76 3.8.2 Structure 77 3.8.3 Mechanism of catalysis 78 3.8.4 Variation and expression 80 3.8.5 FMOs in drug development 80 3.9 How CYP isoforms operate in vivo 81 3.9.1 Illustrative use of structures 82 3.9.2 Primary purposes of CYPs 82 3.9.3 Role of oxidation 83 3.9.4 Summary of CYP operations 84 3.10 Aromatic ring hydroxylation 84 3.10.1 Nature of aromatics 84 3.10.2 Oxidation of benzene 85 3.11 Alkyl oxidations 86 3.11.1 Saturated alkyl groups 86 3.11.2 Unsaturated alkyl groups 87 3.11.3 Pathways of alkyl metabolism 89 3.12 Rearrangement reactions 90 3.12.1 Dealkylations 90 3.12.2 Deaminations 93 3.12.3 Dehalogenations 94 3.13 Other oxidation processes 94 3.13.1 Primary amine oxidations 94 3.13.2 Oxidation of alcohol and aldehydes 96 3.13.3 Monoamine oxidase (MAO) 96 3.14 Control of CYP metabolic function 97 References 97