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Drug Metabolizing Enzymes : Cytochrome P450 and Other Enzymes in Drug Discovery and Development - Jae Lee

Drug Metabolizing Enzymes

Cytochrome P450 and Other Enzymes in Drug Discovery and Development

By: Jae Lee (Editor), R. Scott Obach (Editor), Michael B. Fisher (Editor)

Hardcover Published: 3rd September 2003
ISBN: 9780824742935
Number Of Pages: 608

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Critical in the elimination of drugs and other xenobiotics from the body, cytochrome P450 has strong bearing on scientific assessments of genetic polymorphism in metabolism, possible drug-drug interactions, and bioavailability of candidate drugs. This text systematizes findings on P450 and similar enzymes - as well as parallel issues shaping the pharmaceutical industry - to promote the next generation of safer, more effective drugs.

Editors' Prefacep. xiii
Forewordp. xv
Dioxygen Activation by Cytochromes P450: A Role for Multiple Oxidants in the Oxidation of Substratesp. 1
Introductionp. 1
Active Oxidant(s) in Cyp Reactionsp. 6
Heme-Hydroperoxo as an Oxidantp. 19
Heme-Superoxo as Active Oxidantp. 24
The Two-State Theoryp. 25
Conclusionsp. 27
Referencesp. 27
Application of LC/MS, LC/NMR, NMR and Stable Isotopes in Identifying and Characterizing Metabolitesp. 33
Separation of Metabolites from Endogenous Componentsp. 36
Liquid Chromatography/Mass Spectrometryp. 39
Nuclear Magnetic Resonance (NMR)p. 46
Specific Examplesp. 51
Conclusionsp. 81
Referencesp. 83
Bioactivationp. 87
Introductionp. 87
Involvement of Reactive Metabolites in Adverse Reactionsp. 88
Enzyme Systems Responsible for Metabolic Activationp. 93
Types of Reactive Metabolitesp. 94
The Use of Bioactivation Screens for Lead Drug Selectionp. 135
Summary and Conclusionsp. 138
Referencesp. 139
Chemically Reactive Metabolites in Drugdiscovery and Developmentp. 147
Referencesp. 154
Cytochrome P450 and its Place in Drug Discovery and Developmentp. 155
Introductionp. 155
From Single Enzyme to Superfamily of Human Isoformsp. 155
Inhibition of Human Isoformsp. 160
Induction of Human Isoformsp. 163
Diversity of Human Isoformsp. 166
Response to P450 Metabolism in Drug Designp. 168
P450 as a Drug Targetp. 173
Summaryp. 176
Referencesp. 176
Cytochrome P450 in Laboratory Animal Speciesp. 179
Introductionp. 179
Laboratory Animal Models as Predictors of Human Metabolismp. 179
From Animal to Man: Comparison of Catalytic Selectivity by One Subfamilyp. 185
Regulation of Laboratory Animal Cytochrome P450p. 192
Non-Native Animal Modelsp. 197
Conclusionsp. 201
Referencesp. 202
Typical and Atypical Enzyme Kineticsp. 211
Introductionp. 212
The Michaelis-Menten Approach for Analysis of Enzyme Kinetic Datap. 215
Multisite Approach for Analysis of A Typical Kinetic Datap. 227
In Vivo Relevance of in Vitro Atypical Kinetics and Current Perspectivep. 248
Referencesp. 251
Cytochrome P450 Reaction Phenotypingp. 255
Introductionp. 256
Effect of Incubation Conditions on Reaction Phenotypingp. 262
Enzyme Kinetics and Reaction Phenotypingp. 266
Correlation Analysisp. 274
Expressed P450S and Reaction Phenotypingp. 281
Chemical Inhibitors and Reaction Phenotypingp. 285
Antibodiesp. 294
Concluding Remarksp. 299
Acknowledgementsp. 300
Referencesp. 300
Drug-Drug Interactions and the Cytochromes P450p. 311
Introductionp. 311
In Vitro Drug-Drug Interactions: Determining the Potential of an Nce to Inhibit the Cypsp. 317
In Vivo Drug-Drug Interaction Studiesp. 322
Conclusionp. 332
Referencesp. 332
CYP Gene Induction by Xenobiotics and Drugsp. 337
Introductionp. 337
Clinical and Pharmacological Consequences of CYP1-3 Gene Induction in Manp. 338
Mechanisms of CYP Gene Inductionp. 339
In Vitro Systems to Screen CYP Inducersp. 354
In Vivo Evaluation of CYP Induction in Manp. 360
Conclusionp. 364
Referencesp. 365
Cytochrome P450 Pharmacogeneticsp. 375
Introductionp. 375
P450 Pharmacogeneticsp. 381
Pharmacogenetics: Promise Versus Practicep. 412
Conclusionsp. 414
Acknowledgementp. 415
Referencesp. 415
Role of Intestinal Cytochromes P450 in Drug Dispositionp. 421
Introductionp. 422
Intestinal Cytochromes P450p. 429
Summary and Perspectivep. 445
Referencesp. 446
Prediction of Hepatic Clearance in Humans from Experimental Animals and in Vitro Datap. 453
Introductionp. 454
Strategy for the Prediction of Hepatic Clearance in Humansp. 458
Optimization of Metabolic Clearance by Structure Modificationp. 474
Conclusionp. 477
Referencesp. 478
Non-P450 Mediated Oxidative Metabolism of Xenobioticsp. 483
Flavin-Containing Monooxygenases (FMOs)p. 484
Monoamine Oxidasesp. 499
Molybdenum Hydroxylasesp. 511
Carbonyl Reductases and Alcohol-and Aldehyde Dehydrogenasesp. 527
Referencesp. 529
The Role of Sulfotransferases (Sults) and Udp-Glucuronosyltransferases (Ugts) in Human Drug Clearance and Bioactivationp. 541
General Introductionp. 541
Introduction to the Sulfotransferase Enzyme Familyp. 541
Assay of Sulfotransferase Activityp. 543
Molecular Tools Available to Study Sulfotransferasesp. 545
Role of Sulfation in Bioactivation of Drugs and Other Xenobioticsp. 548
Sulfotransferase Pharmacogeneticsp. 550
Introduction to the Udp-Glucuronosyltransferase Enzyme Familyp. 551
Reaction Mechanism/Structurep. 552
Enzymology and Methodologiesp. 554
Regulationp. 557
Pharmacogeneticsp. 558
Role in Drug and Xenobiotic Metabolismp. 561
Conclusionsp. 566
Acknowledgementsp. 567
Referencesp. 567
Indexp. 577
Table of Contents provided by Ingram. All Rights Reserved.

ISBN: 9780824742935
ISBN-10: 0824742931
Audience: General
Format: Hardcover
Language: English
Number Of Pages: 608
Published: 3rd September 2003
Publisher: Taylor & Francis Inc
Country of Publication: US
Dimensions (cm): 24.13 x 17.15  x 3.81
Weight (kg): 1.14
Edition Number: 1

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