Introduction

Our knowledge of the various human drug metabolizing enzyme systems continues to grow. In recent years, this expansion in knowledge has been fueled by significant advances in molecular biology, the increased availability of human tissue, and the development of reliable model systems and sensitive assay methods for studying drug metabolism in vitro. In fact, in vitro methodology has become increasingly ‘‘standardized’’ and has been widely accepted by academic institutions, the pharmaceutical industry and regulatory agencies. However, while in vitro approaches can be used to screen large numbers of compounds preclinically, it is recognized that accurate forecasting of drug–drug interaction is predicated on sound knowledge of in vivo pharmacokinetics and the availability of validated in vitro–in vivo correlations. Towards this end, the purpose of Drug–Drug Interactions is to relate pharmacokinetic concepts to the Michaelis–Menten kinetics describing in vitro enzyme-catalyzed biotransformation reactions. With kinetics as a foundation, the topic of drug–drug interactions is presented in terms of the various in vitro models, representative enzyme systems (e.g., cytochromes P450 and UDP glucuronosyl transferases), and approaches (e.g., kinetics-based in vitro–in vivo correlations, computer-aided molecular modeling studies and informational databases). Although the subject matter focuses on metabolism-based drug–drug interactions resulting from inhibition and induction of drug-metabolizing enzymes, it is acknowledged that drug–drug interactions can occur via other mechanisms (e.g., competition for drug transporters and binding sites on plasma proteins, or pharmacodynamic drug–drug interactions). An additional objective of this book is to present the subject of drug–drug interactions from preclinical, clinical, toxicological, regulatory, and marketing perspectives. Therefore, it is hoped that Drug–Drug Interactions will be useful to students and seasoned scientists in the fields of molecular biology, pharmacokinetics, enzymology, toxicology, drug metabolism, pharmacology, clinical pharmacology, medicine, and medicinal chemistry. The subject matter will also appeal to those involved in the marketing of drugs. In the end, the book will have achieved its purpose if it serves merely to provoke constructive debate among individuals within these various disciplines.

Contents

1. Introducing Pharmacokinetic and Pharmacodynamic Concepts
Malcolm Rowland
2. In Vitro Enzyme Kinetics Applied to Drug-Metabolizing
Enzymes
Kenneth R. Korzekwa
3. Human Cytochromes P450 and Their Role in Metabolism-Based
Drug–Drug Interactions
Stephen E. Clarke and Barry C. Jones
4. Review of Human UDP-Glucuronosyltransferases and Their
Role in Drug–Drug Interactions
Rory P. Remmel
5. Drug–Drug Interactions Involving the Membrane Transport
Process
Hiroyuki Kusuhara and Yuichi Sugiyama

6. In Vitro Models for Studying Induction of Cytochrome P450

Enzymes

Jose M. Silva and Deborah A. Nicoll-Griffith

7. In Vitro Approaches for Studying the Inhibition of DrugMetabolizing Enzymes and Identifying the Drug-Metabolizing Enzymes Responsible

for the Metabolism of Drugs

Ajay Madan, Etsuko Usuki, L. Alayne Burton, Brian W. Ogilvie,

and Andrew Parkinson

8. The Role of P-Glycoprotein in Drug Disposition: Significance to

Drug Development

Matthew D. Troutman, Gang Luo, Liang-Shang Gan, and

Dhiren R. Thakker

9. The Role of the Gut Mucosa in Metabolically Based Drug–

Drug Interactions

Kenneth E. Thummel and Danny D. Shen

10. Mechanism-Based Inhibition of Human Cytochromes P450:

In Vitro Kinetics and In Vitro–In Vivo Correlations

David R. Jones and Stephen D. Hall

11. Prediction of Metabolic Drug Interactions: Quantitative or

Qualitative?

Jiunn H. Lin and Paul G. Pearson

12. In Vivo Probes for Studying Induction and Inhibition of

Cytochrome P450 Enzymes in Humans

Grant R. Wilkinson

13. Molecular Modeling Approaches to Predicting Drug Metabolism

and Toxicity

Anton M. ter Laak, Marcel J. de Groot, and Nico P. E.

Vermeulen

14. Development of a Metabolic Drug Interaction Database at the

University of Washington

Sonia P. Carlson, Isabelle Ragueneau-Majlessi, Thomas E.

Bougan, and Rene ´ H. Levy

15. Drug–Drug Interactions: Clinical Perspective

David J. Greenblatt and Lisa L. von Moltke

16. Drug–Drug Interactions: Toxicological Perspectives

Sidney D. Nelson

17. An Integrated Approach to Assessing Drug–Drug Interactions:

A Regulatory Perspective

Shiew-Mei Huang, Peter Honig, Lawrence J. Lesko, Robert

Temple, and Roger Williams

18. Drug–Drug Interactions: Marketing Perspectives

Kevin J. Petty and Jose ´ M. Vega

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