Abstract
Animals are not commonly used to assess drug-drug interactions (DDI) 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 PXR, CAR, CYP3A4/CYP3A7 and CYP2D6 (Tg-Composite), was utilized to investigate the effect of induction mediated by rifampin on the pharmacokinetics of tamoxifen and its metabolites. In human, 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, pre-treatment with rifampin decreased tamoxifen AUC0-8 from 0.82 to 0.20 µM*hr; 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 non-humanized C57BL/6 (WT) 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 while 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, 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.
- The American Society for Pharmacology and Experimental Therapeutics