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PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein.


Mol Pharm. 2013 Jan 29;


Authors: Holmstock N, Gonzalez FJ, Baes M, Annaert P, Augustijns P


Abstract

Rodent models are less suitable for predicting drug-drug interactions at the level of the human intestinal mucosa, especially when nuclear receptors like pregnane X receptor (PXR) are involved. Recently, a transgenic mouse model, expressing both human PXR and CYP3A4, was developed and shown to be a better predictor of CYP3A4 induction by xenobiotics in humans as compared to wild-type mice. In the present study, we tested the hypothesis that this mouse model can also predict PXR-mediated induction of intestinal P-gp in humans. By use of the in situ intestinal perfusion technique with mesenteric blood sampling, the effect of oral rifampicin treatment on intestinal permeability for the HIV protease inhibitor darunavir, a dual CYP3A4/P-gp substrate, was investigated. Rifampicin treatment lowered the intestinal permeability for darunavir by 50 % compared to non-treated mice. The P-gp inhibitor GF120918 increased the permeability for darunavir by 400 % in rifampicin-treated mice, while this was only 56 % in mice that were not treated, thus indicating P-gp induction by rifampicin. The non-specific P450 inhibitor aminobenzotriazole (100 ┬ÁM) did not affect the permeability for darunavir. Quantitative Western blot analysis of the intestinal tissue showed that rifampicin treatment induced intestinal P-gp levels four-fold, while CYP3A4 levels remained unchanged. Oral co-administration of rifampicin with the phytochemical sulforaphane for three days increased the permeability for darunavir by 50 % compared to rifampicin treatment alone. These data show that PXR/CYP3A4-humanized mice can be used to study the inducing effects of xenobiotics on intestinal P-gp.

PMID: 23360470 [PubMed - as supplied by publisher]