Antoine Daniel J, Williams Dominic P, Park B Kevin
University of Liverpool, MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, L69 3GE, UK.
Expert Opin Drug Metab Toxicol. 2008 Nov;4(11):1415-27. doi: 10.1517/17425255.4.11.1415.
Drug-induced liver injury (DILI) represents a major impediment to the development of new drugs and is a leading cause of drug withdrawal. The occurrence of hepatotoxicity has been closely associated with the formation of chemically reactive metabolites. Huge investment has focused on the screening of chemically reactive metabolites to offer a pragmatic approach to produce safer drugs and also reduce drug attrition and prevent market place withdrawal. However, questions surrounding the importance of chemically reactive metabolites still remain. Increasing evidence now exists for the multi-factorial nature of DILI, in particular the role played by the host immune system or disease state in the pathogenesis of DILI. This review aims to evaluate the current measures for the prediction and diagnosis of DILI and to highlight investigations being made to understand the multidimensional nature. Some of the steps being made to generate improved physiological systems to identify more sensitive, reflective mechanism-based biomarkers to aid the earlier identification of DILI and develop safer medicines are also discussed.
药物性肝损伤（DILI）是新药研发的主要障碍，也是药物撤市的主要原因。肝毒性的发生与化学反应性代谢物的形成密切相关。大量投资集中在化学反应性代谢物的筛选上，以提供一种实用的方法来生产更安全的药物，同时减少药物损耗并防止药物从市场撤市。然而，围绕化学反应性代谢物重要性的问题仍然存在。现在越来越多的证据表明DILI具有多因素性质，特别是宿主免疫系统或疾病状态在DILI发病机制中所起的作用。本综述旨在评估目前DILI的预测和诊断措施，并强调为了解其多维性质所做的研究。还讨论了为生成改进的生理系统以识别更敏感、基于机制的反映性生物标志物以帮助早期识别DILI和开发更安全药物所采取的一些步骤。
