医薬品探索ステージにおける胆汁うっ滞リスク評価

抄録

Drug-induced liver injury (DILI) is a major cause of market withdrawal or drug-development discontinuation because of safety concerns. Drug-induced cholestasis (DIC) constitutes a major subgroup of DILI accounting for as much as 50% of all clinical cases of DILI. Bile acid (BA) synthesis occurs in liver cells. As surfactants or detergents, BAs are potentially toxic to cells, and their concentrations are tightly regulated. The disruption of the normal process of bile secretion results in cholestasis. Focusing on cholestasis caused by drug-induced endogenous BAs stasis such as the inhibition of BA transport, we established an in vitro DIC test system using simply two-dimensional cultured HepaRG cells and 12 types of BAs present in the human serum. Based on the investigation using DILI-concern drugs with the bile acid export pump (BSEP) inhibitory potential, the established DIC test system was mostly superior to the Css/BSEP IC₅₀ (＞ 0.1) assessment system, which one of DIC risk criteria. Therefore, it can be widely applicable as a model for the in vitro potential assessment of DIC. In this session, we would like to introduce the established DIC test system and mention to the risk assessment at the drug discovery stage with reference to in-house case studies.