Rifampin-Mediated Induction of Tamoxifen Metabolism in a Humanized PXR-CAR-CYP3A4/3A7-CYP2D6 Mouse Model
Rifampin-Mediated Induction of Tamoxifen Metabolism in a Humanized PXR-CAR-CYP3A4/3A7-CYP2D6 Mouse Model
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DOI：
10.1124/dmd.116.072132
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发表时间：
2016-11-01
影响因子：
3.9
通讯作者：
Ly, Justin
中科院分区：
文献类型：
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作者：
Chang, Jae H.;Chen, John;Ly, Justin
由于药物代谢酶和转运蛋白及其调节途径可能存在种属差异，导致临床可翻译性较差，因此通常不使用动物评估药物间相互作用。在这项研究中，转基因小鼠模型表达人的雄烷X受体（PXR），组成型雄烷受体（CAR），CYP 3A 4/CYP 3A 7，和CYP 2D 6（Tg-复合物）被用来研究诱导利福平介导的他莫昔芬及其代谢产物的药代动力学的影响。在人体中，他莫昔芬主要通过CYP 3A 4和CYP 2D 6代谢，利福平多日治疗使他莫昔芬暴露量降低6.2倍。有趣的是，他莫昔芬代谢物4-羟基他莫昔芬（4 OHT）、N-去甲基他莫昔芬（NDM）和内昔芬的暴露量也减少。在TG复合模型中，利福平预处理使他莫昔芬0 - 8小时时间-浓度曲线下面积（AUC（0-8））从0.82 μ M*h降至0.20 μ M*h，而4 OHT、NDM和内昔芬的AUC（0-8）分别降低了3.4、4.7和1.3倍，反映了临床观察结果。在人源化PXR-CAR（hPXR-CAR）模型中，利福平使他莫昔芬及其代谢产物的AUC（0-8）降低约2倍。相反，在非人源化C57 BL/6（野生型）动物中未观察到利福平的显著调节。在从Tg复合动物肝脏制备的微粒体中测定的体外动力学表明，尽管溶媒和利福平给药组之间的K-m值无差异，但利福平增加了CYP 3A 4介导途径的V-max。这些数据表明，尽管hPXR-CAR模型对利福平有响应，但临床利福平-他莫昔芬相互作用的程度更好地由Tg复合模型表示。因此，Tg复合模型可能是一种合适的工具，用于检查利福平介导的其他化合物（其代谢由CYP 3A 4和/或CYP 2D 6介导）的诱导程度。
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(0-8)) from 0.82 to 0.20 mu M*h, whereas AUC(0-8) 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 AUC(0-8) 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 K-m values were not different between vehicle-and rifampin-treated groups, rifampin increased the V-max 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.