Establishment of a predictive test system for idiosyncratic drug-induced liver injury and study for evaluation of onset biomarkers

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H02616
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Nagoya University
• Principal Investigator: Yokoi Tsuyoshi 名古屋大学, 医学系研究科, 教授 (70135226)
• Co-Investigator(Kenkyū-buntansha): 織田 進吾 名古屋大学, 医学系研究科, 特任助教 (10725534)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 薬物性肝障害 / 肝障害予測 / 医薬品開発 / マイクロRNA / 特異体質性肝障害 / バイオマーカー / 動物モデル

Outline of Final Research Achievements

The final purpose of drug-induced liver injury (DILI) prediction study is to establish a DILI prediction test system that is classified as idiosyncratic DILI, which has no significant dose-dependent onset and very large individual differences. During the three-year research period, we established a model animal for liver injury with methimazole, carbamazepine, enalapril, and faciglifam, and reported the mechanism of its onset. MicroRNA (miRNA) as a biomarker in early plasma was investigated by NGS using a rat liver injury model, and as a result, a plasma miRNA capable of discriminating pathologenesis of hepatocytotoxicity, cholestasis and fatty liver was suggested. In addition, we reported that the information from in vivo animal model was applied to an in vitro cell-based test system.

Free Research Field

医薬品安全性学

Academic Significance and Societal Importance of the Research Achievements

新薬が市場から撤退する理由の約30％は薬物性肝障害の発症であり、患者や製薬会社のみならず社会にとっても大きな損失である。本研究では、研究代表者らが最近個々の臨床での肝障害発症被疑薬で報告している反応性代謝物の生成反応と免疫や炎症因子の関与を考慮した非臨床肝障害予測試験系を更に発展させ、新規化合物の細胞レベルおよび実験動物レベルでの実践的で統括的な肝障害予測試験系を提案・評価することを目的とした。その結果、多くの代表的な臨床肝障害被疑薬の動物モデルと発症機序を明らかにできたことより、創薬における非臨床研究に寄与できると考えられる。