代谢
Selumetinib 在肝脏中大量代谢，提出的代谢途径如下：Selumetinib 的酰胺功能团水解产生含有羧酸的 M15（AZ13326637）。从母体化合物中消除乙二醇部分，形成主要的酰胺代谢物 M14（AZ12791138）。酰胺水解将 M14 转化为 M15，M14 的葡萄糖苷酸化和进一步氧化产生 M2、M6 和 M1，M14 的N-去甲基化产生 M12。认为酰胺葡萄糖苷酸（M2）是主要的循环代谢物。Selumetinib 的去甲基化产生具有药理活性的 M8（AZ12442942），M8 的进一步氧化导致 M11。M8 的葡萄糖苷酸化产生 M3 或 M5，从 M8 中消除乙二醇部分产生初级酰胺，生成 M12。尽管 N-去甲基化代谢物（M8）仅占循环代谢物的不到 10%，但它负责大约 21-35% 的观察到的药理活性。核糖结合将 M12 转化为 M9，而 M12 的氧化导致 M10 和 M13 代谢物。M10 的葡萄糖苷酸化产生 M1。Selumetinib 直接葡萄糖苷酸化产生 M4 或 M7，它们最终都可以转化为 M3 和 M5 代谢物。
Selumetinib is heavily metabolized in the liver and the proposed metabolic pathway is as follows: Hydrolysis of selumetinib’s amide functional group produces M15 (AZ13326637), which contains a carboxylic acid. Elimination of the ethanediol moiety from the parent compound results in the formation of the primary amide M14 (AZ12791138) metabolite. Amide hydrolysis transforms M14 into M15, glucuronidation and further oxidation of M14 leads to M2, M6 and M1, and N-demethylation of M14 produces M12. The amide glucuronide (M2) is thought to be the major circulating metabolite. Demethylation of selumetinib produces the pharmacologically active M8 (AZ12442942), and further oxidation of M8 leads to M11. Glucuronidation of M8 produces M3 or M5, and elimination of the ethanediol moiety from M8 results in a primary amide, producing M12. Although the N-demethylated metabolite (M8) accounts for <10% of the circulating metabolites, it is responsible for approximately 21-35% of any observed pharmacological activity. Ribose conjugation transforms M12 into M9, while oxidation of M12 leads to M10 and M13 metabolites. Glucuronidation of M10 produces M1. Direct glucuronidation of selumetinib produces M4 or M7, which can both eventually transform into M3 and M5 metabolites.
来源:DrugBank
