Preface

iii

Contributors

ix

PART I

FUNDAMENTAL ASPECTS OF DRUG METABOLISM

1

The Evolution of Drug Metabolism Research   Patrick J. Murphy

7

2

Pharmacokinetics of Drug Metabolites   Philip C. Smith

17

3

Hepatic Architecture: Functional and Subcellular Correlates   Felix A. de la Iglesia and Jeffrey R. Haskins

61

4

The Cytochrome P450 Oxidative System   Paul R. Ortiz de Montellano

85

5

Transformation Enzymes: Oxidative; Non-P450   Carrie M. Mosher and Allan E. Rettie

109

6

UDP-Glucuronosyltransferases   Rory P. Remmel, Jin Zhou, and Upendra A. Argikar

137

PART II

FACTORS WHICH AFFECT DRUG METABOLISM

7

Pharmacogenetics   Ann K. Daly

179

8

Inhibition of Drug Metabolizing Enzymes   F. Peter Guengerich

203

9

The Ontogeny of Drug Metabolizing Enzymes/Pediatric Exclusivity   Ronald N. Hines

227

10

Sites of Extra Hepatic Metabolism, Part I: Lung   Christopher A. Reilly and Garold S. Yost

243

11

Sites of Extra Hepatic Metabolism, Part II: Gut   Mary F. Paine

273

12

Sites of Extra Hepatic Metabolism, Part III: Kidney   Lawrence H. Las

299

13

Sites of Extra Hepatic Metabolism, Part IV: Brain   Ying Wang, Jordan C. Bell, and Henry W. Strobel

327

PART III

TECHNOLOGIES TO STUDY DRUG METABOLISM

14

LC-MS Analysis in Drug Metabolism Studies   Stacy L. Gelhaus and Ian A. Blair

355

15

The Practice of NMR Spectroscopy in Drug Metabolism Studies   Ian D. Wilson, John C. Lindon, and Jeremy K. Nicholson

373

16

Applications of Recombinant and Purified Human Drug-Metabolizing Enzymes: An Industrial Perspective   Ming Yao, Mingshe Zhu, Shu-Ying Chang, Donglu Zhang, and A. David Rodrigues

393

17

In Vitro Metabolism: Subcellular Fractions   Michael A. Mohutsky, Steven A. Wrighton, and Barbara J. Ring

445

18

In Vitro Metabolism: Hepatocytes   Michael W. Sinz

465

19

Drug Interaction Studies in the Drug Development Process: Studies In Vitro   R. Scott Obach and Robert L. Walsky

493

20

Enzyme Induction Studies in Drug Discovery & Development   J. Greg Slatter and Leslie J. Dickmann

521

21

Experimental Characterization of Cytochrome P450 Mechanism Based Inhibition   Dan Rock, Michael Schrag, and Larry C. Wienkers

541

PART IV

APPLICATIONS OF METABOLISM STUDIES IN DRUG DISCOVERY AND DEVELOPMENT

22

Clinical Drug Metabolism   Kirk R. Henne, George R. Tonn, William F. Pool, and Bradley K. Wong

571

23

Minimizing Metabolic Activation in Drug Discovery   Sanjeev Kumar and Thomas A. Baillie

597

24

Kinetic Differences between Generated and Preformed Metabolites: A Dilemma in Risk Assessment   Thomayanl Prueksaritanonl and Jiunn H. Lin

619

25

The Use of Transgenic Animals to Study Drug Metabolism   Colin J. Henderson, C. Roland Wolf, and Nico Scheer

637

26

Preclinical Pharmacokinetic Models for Drug Discovery and Development   Kevin L. Salyers

659

Index

675