RT Journal Article
SR Electronic
T1 Rifampin-Mediated Induction of Tamoxifen Metabolism in a Humanized PXR-CAR-CYP3A4/3A7-CYP2D6 Mouse Model
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1736
OP 1741
DO 10.1124/dmd.116.072132
VO 44
IS 11
A1 Jae H. Chang
A1 John Chen
A1 Liling Liu
A1 Kirsten Messick
A1 Justin Ly
YR 2016
UL http://dmd.aspetjournals.org/content/44/11/1736.abstract
AB Animals are not commonly used to assess drug-drug interactions due to poor clinical translatability arising from species differences that may exist in drug-metabolizing enzymes and transporters, and their regulation pathways. In this study, a transgenic mouse model expressing human pregnane X receptor (PXR), constitutive androstane receptor (CAR), CYP3A4/CYP3A7, and CYP2D6 (Tg-composite) was used to investigate the effect of induction mediated by rifampin on the pharmacokinetics of tamoxifen and its metabolites. In humans, tamoxifen is metabolized primarily by CYP3A4 and CYP2D6, and multiple-day treatment with rifampin decreased tamoxifen exposure by 6.2-fold. Interestingly, exposure of tamoxifen metabolites 4-hydroxytamoxifen (4OHT), N-desmethyltamoxifen (NDM), and endoxifen also decreased. In the Tg-composite model, pretreatment with rifampin decreased tamoxifen area under the time-concentration curve between 0 and 8 hours (AUC0-8) from 0.82 to 0.20 µM*h, whereas AUC0-8 of 4OHT, NDM, and endoxifen decreased by 3.4-, 4.7-, and 1.3-fold, respectively, mirroring the clinic observations. In the humanized PXR-CAR (hPXR-CAR) model, rifampin decreased AUC0-8 of tamoxifen and its metabolites by approximately 2-fold. In contrast, no significant modulation by rifampin was observed in the nonhumanized C57BL/6 (wild-type) animals. In vitro kinetics determined in microsomes prepared from livers of the Tg-composite animals showed that, although Km values were not different between vehicle- and rifampin-treated groups, rifampin increased the Vmax for the CYP3A4-mediated pathways. These data demonstrate that, although the hPXR-CAR model is responsive to rifampin, the extent of the clinical rifampin-tamoxifen interaction is better represented by the Tg-composite model. Consequently, the Tg-composite model may be a suitable tool to examine the extent of rifampin-mediated induction for other compounds whose metabolism is mediated by CYP3A4 and/or CYP2D6.