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Vol. 31, Issue 5, 548-558, May 2003

Expression of the Human CYP3A4 Gene in the Small Intestine of Transgenic Mice: In Vitro Metabolism and Pharmacokinetics of Midazolam

Camille P. Granvil,1 Ai-Ming Yu, Guillermo Elizondo,2 Taro E. Akiyama,3 Connie Cheung, Lionel Feigenbaum, Kristopher W. Krausz, and Frank J. Gonzalez

Laboratory of Metabolism (C.P.G., A.M.Y., G.E., T.E.A., C.C., K.W.K., F.J.G.) and Laboratory of Animal Resources (L.F.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Human cytochrome P450 3A4 (CYP3A4) is the most abundant hepatic and intestinal phase I drug-metabolizing enzyme, and participates in the oxidative metabolism of approximately 50% of drugs on the market. In the present study, a transgenic-CYP3A4 (Tg-CYP3A4) mouse model that expresses CYP3A4 in the intestine and is phenotypically normal was generated, which was genotyped by both polymerase chain reaction and Southern blotting. Intestinal microsomes prepared from Tg-CYP3A4 mice metabolized midazolam (MDZ) to 1'-hydroxymidazolam about 2 times, and to 4-hydroxymidazolam around 3 times faster than that from wild-type (WT) mice. These increased MDZ hydroxylation activities were completely inhibited by an anti-CYP3A4 monoclonal antibody. The time course of plasma MDZ and its metabolite concentrations was measured after intravenous (0.25 mg/kg) and oral (2.5 mg/kg) administration of MDZ, and pharmacokinetic parameters were estimated by fitting to a noncompartmental model. Pretreatment with ketoconazole increased orally dosed MDZ maximum plasma concentration (Cmax), time of the maximum concentration, area under the plasma concentration-time curve from zero to infinity (AUC0-infinity ), and elimination half-life (t1/2) to 3.2-, 1.7-, 7.7-, 2-fold, and decreased MDZ apparent oral clearance about 8-fold in Tg-CYP3A4 mice. The ratios of MDZ Cmax, AUC0-infinity , t1/2 and bioavailability between Tg-CYP3A4 and WT mice after the oral dose of MDZ were 0.3, 0.6, 0.5, and 0.5, respectively. These results suggest that this Tg-CYP3A4 mouse would be an appropriate in vivo animal model for the evaluation of human intestine CYP3A4 metabolism of drug candidates and potential food-drug and drug-drug interactions in preclinical drug development.

1 Current address: CombinatoRx Inc., 650 Albany St., Boston, MA 02118.

2 Current address: Departamento De Farmacologia Y Toxicologia, Seccion De Toxicologia Ambiental, Cinvestav-IPN, AP 14-740, México D.F. 07000.

3 Current address: Merck Research Laboratories, 126 East Lincoln Ave., Rahway, NJ 07065.

Copyright © 2003 by U.S. Government


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