Cyprotex Discovery Ltd., No.24 Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
Alderley Park Accelerator, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
Arch Toxicol. 2020 Aug;94(8):2559-2585. doi: 10.1007/s00204-020-02763-w. Epub 2020 May 6.
Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.
早期识别与新化学实体（NCEs）相关的毒性对于防止药物开发后期淘汰至关重要。肝损伤仍然是临床试验和上市后撤回药物的主要原因，反映了传统临床前动物模型与人类临床结果之间较差的转化。因此，近年来，临床前策略已经发展到纳入更复杂的基于人类体外细胞的多参数终点模型。这篇综述旨在强调在药物发现中提高人类肝毒性预测所采用的策略的演变，并将其与我们实验室的最新活动进行比较/对比。还详细阐述了人类暴露和肝摄取转运体（如 OATPs、OAT2）的关键作用。
