Department of DMPK/Tox, Shanghai Hengrui Pharmaceutical, No. 279 Wenjing Road, Shanghai 200245, China.
Department of DMPK/Tox, Shanghai Hengrui Pharmaceutical, No. 279 Wenjing Road, Shanghai 200245, China.
Drug Discov Today. 2023 Jul;28(7):103621. doi: 10.1016/j.drudis.2023.103621. Epub 2023 May 17.
The formation of reactive metabolites (RMs) is thought to be one of the pathogeneses for some idiosyncratic adverse drug reactions (IADRs) which are considered one of the leading causes of some drug attritions and/or recalls. Minimizing or eliminating the formation of RMs via chemical modification is a useful tactic to reduce the risk of IADRs and time-dependent inhibition (TDI) of cytochrome P450 enzymes (CYPs). The RMs should be carefully handled before making a go-no-go decision. Herein, we highlight the role of RMs in the occurrence of IADRs and CYP TDI, the risk of structural alerts, the approaches of RM assessment at the discovery stage and strategies to minimize or eliminate RM liability. Finally, some considerations for handling a RM-positive drug candidate are suggested.
活性代谢物（RMs）的形成被认为是某些特异质药物不良反应（IADRs）的发病机制之一，这些不良反应被认为是导致某些药物淘汰和/或召回的主要原因之一。通过化学修饰来最小化或消除 RMs 的形成是降低 IADRs 和细胞色素 P450 酶（CYPs）时间依赖性抑制（TDI）风险的有效策略。在做出去留决策之前，应该仔细处理 RMs。本文重点介绍了 RMs 在 IADRs 和 CYP TDI 中的作用、结构警示的风险、发现阶段 RMs 评估的方法以及最小化或消除 RMs 责任的策略。最后，还提出了一些处理 RMs 阳性药物候选物的注意事项。
