Faculty of Pharmacy, Chiba Institute of Science, 15-8, Shiomi-cho, Choshi, Chiba, 288-0025, Japan.
Faculty of Pharmacy, Chiba Institute of Science, 15-8, Shiomi-cho, Choshi, Chiba, 288-0025, Japan.
Drug Metab Pharmacokinet. 2021 Jun;38:100391. doi: 10.1016/j.dmpk.2021.100391. Epub 2021 Mar 25.
Carboxylesterase (CES) plays an important role in the hydrolysis metabolism of ester-type drugs and prodrugs. In this study, we investigated the change in the hydrolysis rate of hCE1 by focusing on the steric hindrance of the ester structure and the electron density. For 26 kinds of synthesized indomethacin prodrugs, the hydrolytic rate was measured in the presence of human liver microsomes (HLM), human small intestine microsomes (HIM), hCE1 and hCE2. The synthesized prodrugs were classified into three types: an alkyl ester type that is specifically metabolized by hCE1, a phenyl ester type that is more easily metabolized by hCE1 than by hCE2, and a carbonate ester type that is easily metabolized by both hCE1 and hCE2. The hydrolytic rate of 1-methylpentyl (hexan-2-yl) ester was 10-times lower than that of 4-methylpentyl ester in hCE1 solution. hCE2 was susceptible to electron density of the substrate, and there was a difference in the hydrolysis rate of up to 3.5-times between p-bromophenyl ester and p-acetylphenyl ester. By changing the steric hindrance and electron density of the alkoxy group, the factors that change the hydrolysis rate by CES were elucidated.
羧酸酯酶（CES）在酯类药物和前药的水解代谢中发挥着重要作用。在本研究中，我们通过关注酯结构的空间位阻和电子密度，研究了 hCE1 水解速率的变化。对于 26 种合成的吲哚美辛前药，在人肝微粒体（HLM）、人小肠微粒体（HIM）、hCE1 和 hCE2 的存在下测量了其水解速率。所合成的前药分为三种类型：烷基酯型，其被 hCE1 特异性代谢；芳基酯型，其比 hCE2 更容易代谢；碳酸酯型，其容易被 hCE1 和 hCE2 代谢。在 hCE1 溶液中，1-甲基戊基（己烷-2-基）酯的水解速率比 4-甲基戊基酯低 10 倍。hCE2 易受底物电子密度的影响，p-溴苯基酯和 p-乙酰基苯基酯的水解速率差异高达 3.5 倍。通过改变烷氧基的空间位阻和电子密度，阐明了 CES 改变水解速率的因素。
