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Originally published In Press as doi:10.1074/jbc.M008799200 on October 27, 2000

J. Biol. Chem., Vol. 276, Issue 3, 2256-2262, January 19, 2001
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A Kinetic Model for the Metabolic Interaction of Two Substrates at the Active Site of Cytochrome P450 3A4*

Magang ShouDagger §, Renke Dai§||Dagger Dagger , Dan CuiDagger , Kenneth R. Korzekwa**, Thomas A. BaillieDagger , and Thomas H. RushmoreDagger

From the Dagger  Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486 and || Laboratory of Molecular Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, and ** Camitro Corp., Menlo Park, California 94025

In many cases, CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrates that coexist at the active site. In the present study, we observed that alpha -naphthoflavone (alpha -NF) exhibited a differential effect on CYP3A4-mediated product formation as shown by an increase and decrease, respectively, of the carboxylic acid (P2) and omega -3-hydroxylated (P1) metabolites of losartan, while losartan was found to be an inhibitor of the formation of the 5,6-epoxide of alpha -NF. Thus, to address this problem, a kinetic model was developed on the assumption that CYP3A4 can accommodate two distinct and independent binding domains for the substrates within the active site, and the resulting velocity equations were employed to predict the kinetic parameters for all possible enzyme-substrate species. Our results indicate that the predicted values had a good fit with the experimental observations. Therefore, the kinetic constants can be used to adequately describe the nature of the metabolic interaction between the two substrates. Applications of the model provide some new insights into the mechanism of drug-drug interactions at the level of CYP3A4.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed to this work equally.

Dagger Dagger Present address: Metabolism and pharmacokinetics, D13-06, Bristol-Myers Squibb, P. O. Box 4000, Princeton, NJ 08543.

To whom correspondence should be addressed: Dept. of Drug Metabolism, WP75A-203, Merck Research Laboratories, West Point, PA 19486. E-mail: magang_shou@merck.com. Tel.: 215-652-1899; Fax: 215-652-2410.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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