Rifampin-Mediated Induction of Tamoxifen Metabolism in a Humanized PXR-CAR-CYP3A4/3A7-CYP2D6 Mouse Model

• Published in: Drug metabolism and disposition Vol. 44; no. 11; pp. 1736 - 1741
• Main Authors: Chang, Jae H, Chen, John, Liu, Liling, Messick, Kirsten, Ly, Justin
• Format: Journal Article
• Language: English
• Published: United States 01-11-2016
• Subjects: Animals; Cytochrome P-450 CYP2D6 - metabolism; Cytochrome P-450 CYP3A - metabolism; Female; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic - metabolism; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Steroid - metabolism; Rifampin - pharmacology; Tamoxifen - analogs & derivatives; Tamoxifen - metabolism
• ISSN: 1521-009X; 1521-009X
• DOI: 10.1124/dmd.116.072132

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 (AUC
) from 0.82 to 0.20 µM*h, whereas AUC
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 AUC
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 K
values were not different between vehicle- and rifampin-treated groups, rifampin increased the V
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.