Takakusa Hideo, Masumoto Hiroshi, Makino Chie, Okazaki Osamu, Sudo Kenichi
Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Drug Metab Pharmacokinet. 2009;24(1):100-7. doi: 10.2133/dmpk.24.100.
The metabolic bioactivation of a drug to a reactive metabolite (RM) and its covalent binding to cellular macromolecules is believed to be involved in clinical adverse events, including idiosyncratic drug toxicities. Therefore, it is important to assess the potential of drug candidates to generate RMs and form drug-protein covalent adducts during lead optimization processes. In this study, the RM formation of some marketed drugs were quantitatively assessed by means of a sensitive and robust detection method that we have established using (35)S-glutathione ((35)S-GSH) as a trapping agent. Problematic drugs well-known to generate RMs exhibited a relatively high rate of (35)S-GS-adducts to RM (RM-GS) formation, which contrasted with safe drugs. For practical use in lead optimization processes, a series of new chemical entities were tested and hints on the structural modifications needed in order to minimize their RM formation were provided. Furthermore, the RM-GS formation rates of a number of compounds were compared using their in vitro covalent binding yields to liver proteins determined with (14)C-labeled compounds, demonstrating that the RM-GS formation rate could be a substitute for the covalent binding yield within the same series of compounds.
药物代谢生物活化形成反应性代谢产物（RM）并与细胞大分子共价结合，被认为与临床不良事件有关，包括特异质性药物毒性。因此，在先导化合物优化过程中评估候选药物生成RM和形成药物 - 蛋白质共价加合物的潜力非常重要。在本研究中，我们使用（35）S-谷胱甘肽（（35）S-GSH）作为捕获剂建立了一种灵敏且可靠的检测方法，对一些上市药物的RM形成进行了定量评估。众所周知会生成RM的问题药物表现出相对较高的（35）S-GS-加合物与RM（RM-GS）形成率，这与安全药物形成对比。为了在先导化合物优化过程中实际应用，测试了一系列新化学实体，并提供了关于为尽量减少其RM形成所需结构修饰的线索。此外，使用（14）C标记化合物测定的化合物与肝蛋白的体外共价结合产率，比较了许多化合物的RM-GS形成率，表明在同一系列化合物中，RM-GS形成率可以替代共价结合产率。
