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 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.
Footnotes
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This work was supported by the National Cancer Institute Intramural Research Program, and in part by National Institutes of Health (National Institute of Allergy and Infectious Diseases) Grant U19 AI067773-02.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.012831.
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ABBREVIATIONS: DDI, drug-drug interaction; PXR, pregnane X receptor; P450, cytochrome P450; BAC, bacterial artificial chromosome; hPXR, PXR-humanized transgenic mice; RIF, rifampicin; PCN, pregnenolone 16α-carbonitrile; MDZ, midazolam; PCR, polymerase chain reaction; qPCR, quantitative real-time PCR; Ct, threshold cycle; LC-MS/MS, liquid chromatography-coupled tandem mass spectrometry; Cmax, maximal serum concentration; AUC, area under the concentration-time curve; 1′-OH-MDZ, 1′-hydroxymidazolam; UTR, untranslated region; WT, wild-type; Fwd, forward; Rev, reverse; bp, base pair(s); mAB, monoclonal antibody; Ab, antibody; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; KCZ, ketoconazole.
- Received September 8, 2006.
- Accepted November 7, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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