Yang K, Battista C, Woodhead J L, Stahl S H, Mettetal J T, Watkins P B, Siler S Q, Howell B A
DILIsym Services Inc, Research Triangle Park, North Carolina, USA.
University of North Carolina Institute for Drug Safety Sciences, The Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Clin Pharmacol Ther. 2017 Apr;101(4):501-509. doi: 10.1002/cpt.619. Epub 2017 Feb 17.
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.
药物治疗期间血清胆红素升高可能表明存在整体肝功能障碍以及肝衰竭的高风险。然而，在没有肝损伤的情况下，药物也可通过抑制特定酶/转运蛋白而使血清胆红素升高。我们基于胆红素代谢/转运中已知的功能多态性构建了胆红素处置的机制模型。利用基于生理学的药代动力学（PBPK）模型预测的药物暴露量以及体外测定的酶/转运蛋白抑制常数，我们的模型正确预测了茚地那韦在人和大鼠中引起的高胆红素血症。奈非那韦预计不会引起高胆红素血症，这与临床观察结果一致。接下来，我们研究了一种新的候选药物，该药物在大鼠中既导致血清胆红素升高又有肝损伤的生化证据。模拟结果表明，胆红素升高主要是由于转运蛋白受到抑制，而非整体肝功能障碍。我们得出结论，胆红素的机制建模有助于阐明药物性高胆红素血症的潜在机制，从而区分血清胆红素的良性升高与具有临床意义的升高。
