Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury.
Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury.
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DOI：
10.1016/j.xphs.2015.11.008
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发表时间：
2016-02
影响因子：
3.8
通讯作者：
Brouwer KLR
中科院分区：
文献类型：
--
作者：
Yang K;Guo C;Woodhead JL;St Claire RL 3rd;Watkins PB;Siler SQ;Howell BA;Brouwer KLR
三明治培养的肝细胞（SCH）具有代谢能力，并且具有功能性胆汁网络的基底外侧和小管转运蛋白的正确定位。因此，该细胞模型是一种独特的工具，可用于估计化合物的胆汁排泄。 SCH 已广泛用于评估内源性和外源性化合物和代谢物的肝胆处置。基于 SCH 数据的机制建模能够估计代谢和转运蛋白介导的清除率，这可用于构建基于生理学的药代动力学模型，以预测人类的药物分布和药物相互作用。除了药代动力学研究外，SCH 还被用于研究药物和肝脏产生的代谢物的细胞毒性和生物过程的扰动。人类 SCH 可以提供临床药物性肝损伤 (DILI) 的机制见解。此外，SCH 中生成的数据可以集成到系统药理学模型中，以预测人类潜在的 DILI。本文讨论了 SCH 在研究肝胆药物分布和胆汁酸介导的 DILI 中的应用。举例说明如何使用 SCH 模型中生成的数据建立细胞内胆汁酸和细胞毒性之间的定量关系，以及如何将这些信息纳入用于 DILI 预测的系统药理学模型。
Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction.