RT Journal Article SR Electronic T1 The Pregnane X Receptor Gene-Humanized Mouse: A Model for Investigating Drug-Drug Interactions Mediated by Cytochromes P450 3A JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 194 OP 200 DO 10.1124/dmd.106.012831 VO 35 IS 2 A1 Xiaochao Ma A1 Yatrik Shah A1 Connie Cheung A1 Grace L. Guo A1 Lionel Feigenbaum A1 Kristopher W. Krausz A1 Jeffrey R. Idle A1 Frank J. Gonzalez YR 2007 UL http://dmd.aspetjournals.org/content/35/2/194.abstract AB The most common clinical implication for the activation of the human pregnane X receptor (PXR) is the occurrence of drug-drug interactions mediated by up-regulated cytochromes P450 3A (CYP3A) isozymes. Typical rodent models do not predict drug-drug interactions mediated by human PXR because of species differences in response to PXR ligands. In the current study, a PXR-humanized mouse model was generated by bacterial artificial chromosome (BAC) transgenesis in Pxr-null mice using a BAC clone containing the complete human PXR gene and 5′- and 3′-flanking sequences. In this PXR-humanized mouse model, PXR is selectively expressed in the liver and intestine, the same tissue expression pattern as CYP3A. Treatment of PXR-humanized mice with the PXR ligands mimicked the human response, since both hepatic and intestinal CYP3As were strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16α-carbonitrile, a rodent-specific PXR ligand. In rifampicin-pretreated PXR-humanized mice, an ∼60% decrease was observed for both the maximal midazolam serum concentration (Cmax) and the area under the concentration-time curve, as a result of a 3-fold increase in midazolam 1′-hydroxylation. These results illustrate the potential utility of the PXR-humanized mice in the investigation of drug-drug interactions mediated by CYP3A and suggest that the PXR-humanized mouse model would be an appropriate in vivo tool for evaluation of the overall pharmacokinetic consequences of human PXR activation by drugs. The American Society for Pharmacology and Experimental Therapeutics