ArticleMolecular pharmaceutics2013
PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein.
Article in Molecular pharmaceutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 34 citations in OpenAlex.
- Pregnane X receptor protects against age-related bone loss in males via PI3K/Akt-mediated inhibition of apoptosis.Cell death discovery · 2025Article
- Computer-Aided (In Silico) Modeling of Cytochrome P450-Mediated Food-Drug Interactions (FDI).International journal of molecular sciences · 2022Review
- Predictiveness of the Human-CYP3A4-Transgenic Mouse Model (Cyp3aXAV) for Human Drug Exposure of CYP3A4-Metabolized Drugs.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Disease-drug and drug-drug interaction in COVID-19: Risk and assessment.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2021Review
- The Synergistic Antitumor Effect of Tanshinone IIA Plus Adriamycin on Human Hepatocellular Carcinoma Xenograft in BALB/C Nude Mice and Their Influences on Cytochrome P450 CYP3A4Advances in medicine · 2020Article
- Article
- P450-Humanized and Human Liver Chimeric Mouse Models for Studying Xenobiotic Metabolism and Toxicity.Drug metabolism and disposition: the biological fate of chemicals · 2018Review
- Antiretroviral Drug Metabolism in Humanized PXR-CAR-CYP3A-NOG Mice.The Journal of pharmacology and experimental therapeutics · 2018Article
- Extracts of Immature OrangeFrontiers in pharmacology · 2017Article
- Interactions between CYP3A4 and Dietary Polyphenols.Oxidative medicine and cellular longevity · 2015Review
- Verapamil and rifampin effect on p-glycoprotein expression in hepatocellular carcinoma.Jundishapur journal of natural pharmaceutical products · 2014Article
- Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice.Journal of the American Heart Association · 2014Article
- Islet inflammation in plain sight.Diabetes, obesity & metabolism · 2013Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
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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