Investigation of Drug-Drug Interactions Caused by Human Pregnane X Receptor-Mediated Induction of CYP3A4 and CYP2C Subfamilies in Chimeric Mice with a Humanized Liver
Investigation of Drug-Drug Interactions Caused by Human Pregnane X Receptor-Mediated Induction of CYP3A4 and CYP2C Subfamilies in Chimeric Mice with a Humanized Liver
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DOI：
10.1124/dmd.111.042754
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发表时间：
2012-03-01
影响因子：
3.9
通讯作者：
Ushiki, Junko
中科院分区：
文献类型：
--
作者：
Hasegawa, Maki;Tahara, Harunobu;Ushiki, Junko
细胞色素P450（P450）酶的诱导是药物相互作用（DDI）的危险因素之一。迄今为止，已充分研究了人甾烷X受体（PXR）介导的CYP 3A 4诱导。除CYP 3A 4外，CYP 2C亚家族的表达也受PXR调节，据报道，CYP 2C酶诱导引起的DDI具有重大临床影响。本研究的目的是研究具有人源化肝脏的嵌合小鼠（PXB小鼠）是否可以作为研究PXR介导的CYP 2C亚家族和CYP 3A 4诱导的合适动物模型。我们评价了利福平（RIF）（一种典型的人PXR配体）对PXB小鼠通过盒式给药对四种P450底物药物（三唑仑/CYP 3A 4、吡格列酮/CYP 2C 8、（S）-华法林/CYP 2C 9和（S）-（-）-美芬妥英/CYP 2C 19）的血浆暴露的诱导作用。还通过测量酶活性和mRNA表达水平检查了肝脏中几种药物代谢酶和转运蛋白的诱导。观察到三唑仑、吡格列酮和（S）-（-）-美芬妥英的暴露量显著降低，但（S）-华法林未显著降低。与体内结果相反，所有四种P450亚型，包括CYP 2C 9，通过RIF处理升高。体内和体外研究之间（S）-华法林结果的差异可能归因于本研究中使用的PXB小鼠中CYP 2C 9对（S）-华法林消除的贡献相对较小。总之，PXB小鼠是检查PXR介导的CYP 2C和CYP 3A 4诱导引起的DDI的有用动物模型。
The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(-)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(-)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4.