Role of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714
Role of Hepatic Transporters in the Disposition and Hepatotoxicity of a HER2 Tyrosine Kinase Inhibitor CP-724,714
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DOI：
10.1093/toxsci/kfp033
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发表时间：
2009-04-01
影响因子：
3.8
通讯作者：
Wang, Huifen F.
中科院分区：
文献类型：
--
作者：
Feng, Bo;Xu, Jinghai J.;Wang, Huifen F.
CP-724,714是一种有效和选择性的口服活性HER2酪氨酸激酶抑制剂，由于癌症患者意外的肝毒性而停止临床开发。根据毒性的临床表现，CP-724,714可能通过肝细胞损伤和肝胆汁淤积机制发挥其肝毒性作用。在已建立的人肝细胞模型和体外转运系统中，评价了CP-724,714的直接细胞毒作用、肝胆定位及其对胆汁成分主动小管转运的抑制作用。CP-724,714通过人肝细胞成像检测技术显示出直接的细胞毒性，线粒体被确定为其非靶标毒性的候选细胞器。此外，CP-724,714被人肝细胞迅速吸收，部分是通过主动转运过程，摄取清除量大约是外排清除量的四倍。人类主要的肝脏摄取转运体OATP1B1和外排转运体多药耐药蛋白1(MDR1)和乳腺癌耐药蛋白参与了CP-724,714的肝胆清除。此外，CP-724、714对冷冻保存的人肝细胞和新鲜培养的人肝细胞分别显示出浓度依赖的抑制胆碱-赖氨酰荧光素和牛磺胆酸(TC)外流到小管的作用。同样，CP-724,714抑制表达人胆盐输出泵的膜泡的TC转运，IC50为16 mU M。CP-724,714抑制胆小管主要外流转运体MDR1的IC50与28 mU M相似。这些结果表明，抑制肝脏外流转运体有助于药物和胆汁成分在肝脏中的蓄积，导致肝细胞损伤和肝胆胆汁淤积。这项研究为临床观察到的CP-724,714对肝脏的不良影响提供了可能的解释。
CP-724,714, a potent and selective orally active HER2 tyrosine kinase inhibitor, was discontinued from clinical development due to unexpected hepatotoxicity in cancer patients. Based on the clinical manifestation of the toxicity, CP-724,714 likely exerted its hepatotoxicity via both hepatocellular injury and hepatobiliary cholestatic mechanisms. The direct cytotoxic effect, hepatobiliary disposition of CP-724,714, and its inhibition of active canalicular transport of bile constituents were evaluated in established human hepatocyte models and in vitro transporter systems. CP-724,714 exhibited direct cytotoxicity using human hepatocyte imaging assay technology with mitochondria identified as a candidate organelle for its off-target toxicity. Additionally, CP-724,714 was rapidly taken up into human hepatocytes, partially via an active transport process, with an uptake clearance approximately fourfold higher than efflux clearance. The major human hepatic uptake transporter, OATP1B1, and efflux transporters, multidrug resistance protein 1 (MDR1) and breast cancer resistance protein, were involved in hepatobiliary clearance of CP-724,714. Furthermore, CP-724,714 displayed a concentration-dependent inhibition of cholyl-lysyl fluorescein and taurocholate (TC) efflux into canaliculi in cryopreserved and fresh cultured human hepatocytes, respectively. Likewise, CP-724,714 inhibited TC transport in membrane vesicles expressing human bile salt export pump with an IC50 of 16 mu M. Finally, CP-724,714 inhibited the major efflux transporter in bile canaliculi, MDR1, with an IC50 of similar to 28 mu M. These results suggest that inhibition of hepatic efflux transporters contributed to hepatic accumulation of drug and bile constituents leading to hepatocellular injury and hepatobiliary cholestasis. This study provides likely explanations for clinically observed adverse liver effects of CP-724,714.