PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein.
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.
Laboratory of Drug Delivery and Disposition, KU Leuven , Campus Gasthuisberg, O&N 2, Herestraat 49 box 921, B-3000 Leuven, Belgium.
Nico
N
Holmstock
Frank J
FJ
Gonzalez
Myriam
M
Baes
Pieter
P
Annaert
Patrick
P
Augustijns
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D000069454:Darunavir; D004347:Drug Interactions; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology; D013449:Sulfonamides / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; D015262:Xenobiotics; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C083501:Elacridar; D012293:Rifampin; D000069454:Darunavir