Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym(®), a Mechanistic Model of Drug-Induced Liver Injury.
Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym(®), a Mechanistic Model of Drug-Induced Liver Injury.
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DOI：
10.1002/psp4.12053
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Siler SQ
中科院分区：
文献类型：
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作者：
Longo DM;Yang Y;Watkins PB;Howell BA;Siler SQ
托卡朋和恩他卡朋是儿茶酚-O-甲基转移酶（COMT）抑制剂，作为治疗帕金森病的辅助疗法开发。虽然这两种药物已被证明会导致线粒体功能障碍和胆盐输出蛋白（BSEP）的抑制，但肝损伤仅与使用托卡朋有关。在这里，我们使用多尺度机制模型（DILIsym®）来模拟对托卡朋和恩他卡朋的响应。在接受推荐剂量的托卡朋（200 mg t.i.d.）的模拟群体（SimPops™）中，在2.2%的人群中观察到血清丙氨酸转氨酶（ALT）升高>3×正常上限（ULN）。相比之下，接受推荐剂量恩他卡朋（200 mg 8×天）的模拟患者均未出现血清ALT >3× ULN。此外，DILIsym®分析揭示了可能导致托卡朋介导的肝毒性的患者特异性风险因素。总之，模拟表明，线粒体解偶联效力和肝脏暴露的差异主要是托卡朋和恩他卡朋肝毒性潜力差异的原因。
Tolcapone and entacapone are catechol‐O‐methyltransferase (COMT) inhibitors developed as adjunct therapies for treating Parkinson's disease. While both drugs have been shown to cause mitochondrial dysfunction and inhibition of the bile salt export protein (BSEP), liver injury has only been associated with the use of tolcapone. Here we used a multiscale, mechanistic model (DILIsym®) to simulate the response to tolcapone and entacapone. In a simulated population (SimPops™) receiving recommended doses of tolcapone (200 mg t.i.d.), increases in serum alanine transaminase (ALT) >3× the upper limit of normal (ULN) were observed in 2.2% of the population. In contrast, no simulated patients receiving recommended doses of entacapone (200 mg 8× day) experienced serum ALT >3× ULN. Further, DILIsym® analyses revealed patient‐specific risk factors that may contribute to tolcapone‐mediated hepatotoxicity. In summary, the simulations demonstrated that differences in mitochondrial uncoupling potency and hepatic exposure primarily account for the difference in hepatotoxic potential for tolcapone and entacapone.