首页> 美国卫生研究院文献>CPT: Pharmacometrics Systems Pharmacology >Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym® a Mechanistic Model of Drug‐Induced Liver Injury
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Elucidating Differences in the Hepatotoxic Potential of Tolcapone and Entacapone With DILIsym® a Mechanistic Model of Drug‐Induced Liver Injury

机译:用药物诱导的肝损伤机制模型DILIsym®阐明托卡朋和恩他卡朋的肝毒性潜能差异

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摘要

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.
机译:Tolcapone和entacapone是儿茶酚O甲基转移酶(COMT)抑制剂,是治疗帕金森氏病的辅助疗法。虽然两种药物均已显示出可引起线粒体功能障碍和胆汁盐输出蛋白(BSEP)抑制,但肝损伤仅与使用托卡朋有关。在这里,我们使用了多尺度的机械模型(DILIsym ®)来模拟对tolcapone和entacapone的响应。在接受推荐剂量托卡朋(200 mg t.i.d.)的模拟人群(SimPops™)中,在2.2%的人群中观察到血清丙氨酸转氨酶(ALT)升高> 3倍于正常上限(ULN)。相反,没有模拟患者接受推荐剂量的entacapone(200 mg 8×天)的血清ALT> 3×ULN。此外,DILIsym ®分析显示患者特定的危险因素可能会导致甲苯酮介导的肝毒性。总之,模拟表明线粒体解偶联力和肝暴露的差异主要是造成托卡朋和他卡朋的肝毒性潜力的差异。

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