《DRUG METABOLISM IN DRUG DESIGN AND DEVELOPMENT》质谱电子书
DONGLU ZHANG
MINGSHE ZHU
W. GRIFFITH HUMPHREYS
PART I BASIC CONCEPTS OF DRUG METABOLISM 1
1 Overview: Drug Metabolism in the Modern Pharmaceutical
Industry 3
Scott J. Grossman
1.1 Introduction 3
1.2 Technology 4
1.3 Breadth of Science 5
1.3.1 Chemistry 5
1.3.2 Enzymology and Molecular Biology 6
1.4 Impact of Drug Metabolism on Efficacy and Safety 7
1.4.1 Efficacy 7
1.4.2 Safety 8
1.5 Regulatory Impact and IP Position 9
1.6 Summary 12
References 12
2 Oxidative, Reductive, and Hydrolytic Metabolism of Drugs 15
F. Peter Guengerich
2.1 Introduction 15
2.2 Nomenclature and Terminology 15
2.3 General Features of the Enzymes 16
2.4 Fractional Contributions of Different Enzymes 17
2.5 Oxidation Enzymes 18
2.5.1 Cytochrome P450 (P450, CYP) 18
2.5.2 Flavin-Containing Monooxygenase (FMO) 20
2.5.3 Monoamine Oxidase (MAO) 22
2.5.4 Aldehyde Oxidase and Xanthine Dehydrogenase 23
2.5.5 Peroxidases 24
2.5.6 Alcohol Dehydrogenases (ADH) 25
2.5.7 Aldehyde Dehydrogenases (ALDH) 25
2.6 Reduction 26
2.6.1 P450, ADH 26
2.6.2 NADPH-P450 Reductase 27
2.6.3 Aldo-Keto Reductases (AKR) 28
2.6.4 Quinone Reductase (NQO) 28
2.6.5 Glutathione Peroxidase (GPX) 29
2.7 Hydrolysis 29
2.7.1 Epoxide Hydrolase 29
2.7.2 Esterases and Amidases 30
2.8 Summary 31
References 31
3 Conjugative Metabolism of Drugs 37
Rory Remmel, Swati Nagar and Upendra Argikar
3.1 UDP-Glucuronosyltransferases 37
3.1.1 Location Within the Cell 38
3.1.2 Endogenous Substrates 39
3.1.3 Enzyme Multiplicity 40
3.1.4 Inducibility 42
3.1.5 Pharmacogenetics 56
3.1.6 Experimental Considerations 56
3.1.7 Enzyme Selective Substrates and Inhibitors 59
3.1.8 Drug–Drug Interactions and Glucuronidation 60
3.1.9 Summary 62
3.2 Cytosolic Sulfotransferases 62
3.2.1 Cellular Location and Tissue Expression 64
3.2.2 The SULT Superfamily of Cytosolic Enzymes 64
3.2.3 Inducibility 65
3.2.4 SULT Pharmacogenetics 65
3.2.5 Analytical Detection of Sulfonated Metabolites 67
3.2.6 SULT Inhibitors (Pacifici and Coughtrie, 2005) 68
3.2.7 Drug–Drug Interactions and Sulfonation 68
3.2.8 Summary 72
3.3 Glutathione-S-Transferases 72
3.3.1 General Overview 72
3.3.2 Classification of the GST Enzymes 72
3.3.3 Localization and Expression 73
3.3.4 Reactions Catalyzed by GSTs 73
3.3.5 Regulation of GSTs 73
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