Systems Pharmacology Modeling of Drug-induced Hyperbilirubinemia: Differentiating Hepatotoxicity and Inhibition of Enzymes/Transporters
Systems Pharmacology Modeling of Drug-induced Hyperbilirubinemia: Differentiating Hepatotoxicity and Inhibition of Enzymes/Transporters
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DOI：
10.1002/cpt.619
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发表时间：
2017-04-01
影响因子：
6.7
通讯作者：
Howell, B. A.
中科院分区：
文献类型：
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作者：
Yang, K.;Battista, C.;Howell, B. A.
药物治疗期间血清胆红素升高可能表明全身性肝功能障碍和肝功能衰竭的高风险。然而，在没有肝损伤的情况下，药物也可以通过抑制特定的酶/转运蛋白来提高血清胆红素。我们基于胆红素代谢/转运的已知功能多态性，构建了胆红素处置的机制模型。使用基于生理的药代动力学(PBPK)模型预测药物暴露和体外测定的酶/转运体抑制常数，我们的模型正确地预测了吲哚那韦在人和大鼠中介导的高胆红素血症。奈非那韦被预测不会导致高胆红素血症，这与临床观察一致。接下来，我们检查了一种新的候选药物，它同时导致了大鼠血清胆红素的升高和肝损伤的生化证据。模拟表明，胆红素升高主要是由于转运蛋白的抑制，而不是全球肝功能障碍。我们的结论是，建立胆红素机制模型有助于阐明药物引起高胆红素血症的潜在机制，从而区分良性和临床重要的血清胆红素升高。
Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model-predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir-mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug-induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin.