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Quantitative analysis of drugs induced BSEP inhibition and cholestatic hepatotoxicity

药物引起的 BSEP 抑制和胆汁淤积性肝毒性的定量分析

基本信息

批准号：
23659073
负责人：
HORIE Toshiharu
金额：
$ 2.41万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Challenging Exploratory Research
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659073/
关键词：
薬物動態代謝学国際情報交換薬学薬剤反応生

项目摘要

Drug-induced liver injury (DILI) is a major reason for the dropout of candidate compounds from drug testing and the withdrawal of pharmaceuticals from clinical use. Among the various mechanisms of liver injury, the accumulation of bile acids (BAs) within hepatocytes is thought to be a primary mechanism for the development of DILI. Although bile salt export pump (BSEP) dysfunction is considered a susceptibility factor for DILI, little is known about the relationship between drug-induced BSEP dysfunction and BA-dependent hepatotoxicity. Furthermore, few methods are at hand for the systematic and quantitative evaluation of BA-dependent DILI. This study aimed to construct a model of DILI by employing sandwich-cultured hepatocytes (SCHs). SCHs can be used to assess functions of canalicular transporters such as BSEP and the activity of metabolic enzymes. Here, the impact of 25 test compounds was investigated on BA-dependent cytotoxicity in SCHs. As a result, BA-dependent toxicity was observed for 11 test compounds in SCHs treated in the presence of BAs, while no signs of toxicity were observed for SCHs treated in the absence of BAs. Of the 11 compounds, nine were known BSEP inhibitors. Moreover, for some compounds, an increase in the severity of BA-dependent toxicity was observed in SCHs that were co-treated with 1-aminobenzotriazole, a non-selective inhibitor of cytochrome P450 (CYP450)-mediated drug metabolism. These results indicate that the SCH-based model is likely to prove useful for the evaluation of BA-dependent DILI, including the effects of drug metabolism and BSEP inhibition on liver injury.

药物性肝损伤（DILI）是候选化合物退出药物测试和药物退出临床使用的主要原因。在各种肝损伤机制中，肝细胞内胆汁酸 (BA) 的积累被认为是 DILI 发生的主要机制。尽管胆汁盐输出泵（BSEP）功能障碍被认为是 DILI 的易感因素，但对于药物引起的 BSEP 功能障碍与 BA 依赖性肝毒性之间的关系知之甚少。此外，目前很少有方法可以对 BA 依赖性 DILI 进行系统和定量评估。本研究旨在利用三明治培养肝细胞（SCH）构建 DILI 模型。 SCH 可用于评估 BSEP 等小管转运蛋白的功能和代谢酶的活性。在此，研究了 25 种测试化合物对 SCH 中 BA 依赖性细胞毒性的影响。结果，在存在 BA 的情况下处理的 SCH 中观察到了 11 种测试化合物的 BA 依赖性毒性，而在不存在 BA 的情况下处理的 SCH 中没有观察到毒性迹象。在 11 种化合物中，有 9 种是已知的 BSEP 抑制剂。此外，对于某些化合物，在与 1-氨基苯并三唑（一种细胞色素 P450 (CYP450) 介导的药物代谢的非选择性抑制剂）共同处理的 SCH 中观察到 BA 依赖性毒性的严重程度增加。这些结果表明，基于 SCH 的模型可能对评估 BA 依赖性 DILI 有用，包括药物代谢和 BSEP 抑制对肝损伤的影响。