RT Journal Article SR Electronic T1 Expression of the Human CYP3A4 Gene in the Small Intestine of Transgenic Mice: In Vitro Metabolism and Pharmacokinetics of Midazolam JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 548 OP 558 DO 10.1124/dmd.31.5.548 VO 31 IS 5 A1 Camille P. Granvil A1 Ai-Ming Yu A1 Guillermo Elizondo A1 Taro E. Akiyama A1 Connie Cheung A1 Lionel Feigenbaum A1 Kristopher W. Krausz A1 Frank J. Gonzalez YR 2003 UL http://dmd.aspetjournals.org/content/31/5/548.abstract AB 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-∞), 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 MDZCmax, AUC0-∞,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. U.S. Government