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Drug Metabolism and Disposition Fast Forward
First published on November 8, 2006; DOI: 10.1124/dmd.106.012831

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Received for publication September 11, 2006.
Revised November 6, 2006.
Accepted for publication November 7, 2006.

The PXR-humanized Mouse: a Model for Investigating Drug- drug Interactions Mediated by Cytochromes P450 3A

Xiaochao Ma 1, Yatrik Shah 1, Connie Cheung 1, Grace L. Guo 2, Lionel Feigenbaum 1, Kristopher W. Krausz 1, Jeffrey R. Idle 3, Frank J. Gonzalez 1*

1 National Cancer Institute 2 University of Kansas Medical Center 3 Charles University, Prague

* Address correspondence to: E-mail: fjgonz{at}helix.nih.gov

Abstract

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 cytochrome 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 thecomplete human PXR gene and 5’ and 3’ flanking sequence. 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, as both hepatic and intestinal CYP3A were strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16{alpha}-carbonitrile, a rodent-specific PXR ligand. In rifampicin pretreated PXR-humanized mice,a ~60% decrease was observed for both the maximal midazolam serum concentration(Cmax) and the area under the concentration-time curve (AUC), consequent upon 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 the evaluation of the overall pharmacokinetic consequences of human PXR activation by drugs.


Key words: drug clearance, drug-drug interactions, pharmacokinetics, PXR, transgenic models


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