The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, USA.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
CPT Pharmacometrics Syst Pharmacol. 2014 Jul 9;3(7):e123. doi: 10.1038/psp.2014.21.
Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym was analyzed in the presence of a simulated theoretical BSEP inhibitor. BSEP inhibition in humans is predicted to increase liver concentrations of conjugated chenodeoxycholic acid (CDCA) and sulfate-conjugated lithocholic acid (LCA) while the concentration of other liver BAs remains constant or decreases. On the basis of a sensitivity analysis, the most important unknowns are the level of BSEP expression, the amount of intestinal synthesis of LCA, and the magnitude of farnesoid-X nuclear receptor (FXR)-mediated regulation.
胆汁盐输出泵 (BSEP) 抑制被认为是药物性肝损伤 (DILI) 的一个重要机制。建模可以优先考虑有关胆汁酸 (BA) 动态平衡的知识空白，从而有助于指导实验。DILIsym 是一个 DILI 的机制模型，在其中构建了大鼠和人类的 BA 动态平衡子模型。在给予格列本脲的大鼠中进行了体内实验，并使用这些实验的数据来验证模型。分析了在模拟理论 BSEP 抑制剂存在的情况下 DILIsym 的行为。据预测，BSEP 抑制会增加人肝中结合型鹅脱氧胆酸 (CDCA) 和硫酸结合型石胆酸 (LCA) 的浓度，而其他肝 BA 的浓度保持不变或降低。基于敏感性分析，最重要的未知数是 BSEP 表达水平、LCA 的肠道合成量以及法尼醇 X 核受体 (FXR) 介导的调节幅度。
