Drug metabolizing enzymes : cytochrome P450 and other enzymes in drug discovery and development / edited by Jae S. Lee, R. Scott Obach and Michael B. Fisher.

Format:

Book

Language:

English

Subjects (All):

Drugs--Metabolism.

Drugs.

Enzymes.

Metabolism.

Cytochrome P-450 Enzyme System.

Enzymes--metabolism.

Medical Subjects:

Cytochrome P-450 Enzyme System.

Enzymes--metabolism.

Genre:

Conference papers and proceedings.

Physical Description:

xx, 588 pages : illustrations ; 25 cm

Place of Publication:

Lausanne, Switzerland : FontisMedia SA ; New York : Marcel Dekker, [2003]

Summary:

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.

Contents:

Chapter 1 Dioxygen Activation by Cytochromes P450: A Role for Multiple Oxidants in the Oxidation of Substrates / Alfin D. N. Vaz 1

2 Active Oxidant(s) in Cyp Reactions 6

3 Heme-Hydroperoxo as an Oxidant 19

4 Heme-Superoxo as Active Oxidant 24

5 The Two-State Theory 25

Chapter 2 Application of LC/MS, LC/NMR, NMR and Stable Isotopes in Identifying and Characterizing Metabolites / A. E. Mutlib, John P. Shockcor 33

2 Separation of Metabolites from Endogenous Components 36

3 Liquid Chromatography/Mass Spectrometry 39

4 Nuclear Magnetic Resonance (NMR) 46

5 Specific Examples 51

Chapter 3 Bioactivation / Jack Uetrecht 87

2 Involvement of Reactive Metabolites in Adverse Reactions 88

3 Enzyme Systems Responsible for Metabolic Activation 93

4 Types of Reactive Metabolites 94

5 The Use of Bioactivation Screens for Lead Drug Selection 135

Chapter 4 Chemically Reactive Metabolites in Drugdiscovery and Development / Thomas A. Baillie 147

Chapter 5 Cytochrome P450 and its Place in Drug Discovery and Development / Dennis Smith 155

1 From Single Enzyme to Superfamily of Human Isoforms 155

2 Inhibition of Human Isoforms 160

3 Induction of Human Isoforms 163

4 Diversity of Human Isoforms 166

5 Response to P450 Metabolism in Drug Design 168

6 P450 as a Drug Target 173

Chapter 6 Cytochrome P450 in Laboratory Animal Species / Margit Spatzenegger, Stephanie L. Born, James R. Halpert 179

2 Laboratory Animal Models as Predictors of Human Metabolism 179

3 From Animal to Man: Comparison of Catalytic Selectivity by One Subfamily 185

4 Regulation of Laboratory Animal Cytochrome P450 192

5 Non-Native Animal Models 197

Chapter 7 Typical and Atypical Enzyme Kinetics / J. Brian Houston, Kathryn E. Kenworthy, Aleksandra Galetin 211

2 The Michaelis-Menten Approach for Analysis of Enzyme Kinetic Data 215

3 Multisite Approach for Analysis of A Typical Kinetic Data 227

4 In Vivo Relevance of in Vitro Atypical Kinetics and Current Perspective 248

Chapter 8 Cytochrome P450 Reaction Phenotyping / Larry C. Wienkers, Jeffrey C. Stevens 255

2 Effect of Incubation Conditions on Reaction Phenotyping 262

3 Enzyme Kinetics and Reaction Phenotyping 266

4 Correlation Analysis 274

5 Expressed P450S and Reaction Phenotyping 281

6 Chemical Inhibitors and Reaction Phenotyping 285

7 Antibodies 294

Chapter 9 Drug-Drug Interactions and the Cytochromes P450 / Kenneth A. Bachmann, Barbara J. Ring, Steven A. Wrighton 311

2 In Vitro Drug-Drug Interactions: Determining the Potential of an Nce to Inhibit the Cyps 317

3 In Vivo Drug-Drug Interaction Studies 322

Chapter 10 CYP Gene Induction by Xenobiotics and Drugs / Jean-Marc Pascussi, Sabine Gerbal-Chaloin, Martine Daujat, Lionel Drocourt, Lydiane Pichard-Garcia, Marie-Jose Vilarem, Patrick Maurel, Sylvie Klieber, Francois Torreilles, Martine Bourrie, Francois Guillou, Gerard Fabre 337

2 Clinical and Pharmacological Consequences of CYP1-3 Gene Induction in Man 338

3 Mechanisms of CYP Gene Induction 339

4 In Vitro Systems to Screen CYP Inducers 354

5 In Vivo Evaluation of CYP Induction in Man 360

Chapter 11 Cytochrome P450 Pharmacogenetics / Robert L. Haining, Aiming Yu 375

2 P450 Pharmacogenetics 381

3 Pharmacogenetics: Promise Versus Practice 412

Chapter 12 Role of Intestinal Cytochromes P450 in Drug Disposition / Mary F. Paine, Kenneth E. Thummel 421

2 Intestinal Cytochromes P450 429

Chapter 13 Prediction of Hepatic Clearance in Humans from Experimental Animals and in Vitro Data / Masato Chiba, Yoshihiro Shibata, Hiroyuki Takahashi, Yasuyuki Ishii, Yuichi Sugiyama 453

2 Strategy for the Prediction of Hepatic Clearance in Humans 458

3 Optimization of Metabolic Clearance by Structure Modification 474

Chapter 14 Non-P450 Mediated Oxidative Metabolism of Xenobiotics / Dieter Lang, Amit S. Kalgutkar 483

1 Flavin-Containing Monooxygenases (FMOs) 484

2 Monoamine Oxidases 499

3 Molybdenum Hydroxylases 511

4 Carbonyl Reductases and Alcohol-and Aldehyde Dehydrogenases 527

Chapter 15 The Role of Sulfotransferases (Sults) and Udp-Glucuronosyltransferases (Ugts) in Human Drug Clearance and Bioactivation / Michael W.H. Coughtrie, Michael B. Fisher 541

Introduction to the Sulfotransferase Enzyme Family 541

1 Assay of Sulfotransferase Activity 543

2 Molecular Tools Available to Study Sulfotransferases 545

3 Role of Sulfation in Bioactivation of Drugs and Other Xenobiotics 548

4 Sulfotransferase Pharmacogenetics 550

5 Introduction to the Udp-Glucuronosyltransferase Enzyme Family 551

6 Reaction Mechanism/Structure 552

7 Enzymology and Methodologies 554

8 Regulation 557

9 Pharmacogenetics 558

10 Role in Drug and Xenobiotic Metabolism 561.

Notes:

Includes bibliographical references and index.

ISBN:

0824742931

OCLC:

53119830