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PXR/CYP3A4-Humanized Mice for Studying Drug–Drug Interactions Involving Intestinal P-Glycoprotein

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Laboratory of Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49 box 921, B-3000 Leuven, Belgium
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Building 37, Room 3106, Bethesda, Maryland 20892, United States
§ Laboratory of Cell Metabolism, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49 box 823, B-3000 Leuven, Belgium
*Tel: +32-16-330301, Fax: +32-16-330305. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2013, 10, 3, 1056–1062
Publication Date (Web):January 29, 2013
https://doi.org/10.1021/mp300512r
Copyright © 2013 American Chemical Society

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    Abstract

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    Rodent models are less suitable for predicting drug–drug interactions at the level of the human intestinal mucosa, especially when nuclear receptors such as 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 that in nontreated mice. The P-gp inhibitor GF120918 increased the permeability for darunavir by 400% in rifampicin-treated mice, whereas this was only 56% in mice that were not treated, thus indicating P-gp induction by rifampicin. The nonspecific P450 inhibitor aminobenzotriazole (100 μM) did not affect the permeability for darunavir. Quantitative Western blot analysis of the intestinal tissue showed that rifampicin treatment induced intestinal P-gp levels 4-fold, while CYP3A4 levels remained unchanged. Oral co-administration of rifampicin with the phytochemical sulforaphane for 3 days increased the permeability for darunavir by 50% compared to that with 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.

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