反应性代谢产物的研究进展

Advances in research on the reactive metabolites

大部分药物经体内代谢转化为无活性产物排出体外,部分药物经药物代谢酶转化为活性代谢产物和反应性代谢产物,其中反应性代谢产物可与肝细胞内大分子共价结合,通过不同的机制造成药物诱导的器官损伤。鉴别这些反应性代谢产物对于设计候选新药的毒性控制以及临床用药非常重要,本综述概述了反应性代谢产物的分类、其引起的药物毒性以及目前高通量搜索和鉴定反应性代谢产物等相关实验进展,讨论了处理反应性代谢产物的策略及本领域未来的发展。

Most drugs are changed to inactive metabolites in vivo and then excreted, while some drugs are transformed into active metabolites and reactive metabolites through metabolite enzymes＇ bioactivation. The reactive metabolites can covalently modify proteins, which is considered as an initial step that may lead to drug-induced organ toxicity. So characterization of reactive metabolites is critical for designing new drug candidates with improved toxicological profiles and clinical applications. In this review, a brief description of reactive metabolites is followed by a discussion on the active metabolite-induced toxicity. Experimental approaches employed for high-throughput screening and characterization of reactive metabolite formation are also described, along with strategies for dealing with reactive metabolites in drug development and clinical treatment. In conclusion, the challenges and future needs in this field of research are discussed.