College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
Central Research Institute, Boryung Pharm. co., Ltd. Ansan, Gyeonggi 425-839, Republic of Korea.
Food Chem Toxicol. 2018 May;115:375-384. doi: 10.1016/j.fct.2018.03.036. Epub 2018 Mar 26.
Fimasartan (FMS), an angiotensin II receptor antagonist, is metabolized to FMS S-oxide, FMS N-glucuronide, oxidative desulfurized FMS (BR-A-557), and hydroxy-n-butyl FMSs. The purpose of this study was to characterize enzymes involved in NADPH-dependent FMS metabolism using recombinant enzymes such as cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), as well as selective chemical inhibitors. The results showed that CYP, but not FMO, plays a major role in FMS metabolism. CYP2C9, CYP3A4, and CYP3A5 were involved in the formation of FMS S-oxide, which was further metabolized to BR-A-557 by CYP3A4/5. CYP2C9 played an exclusive role in n-butyl hydroxylation. The specificity constant (kcat/Km) values for S-oxidation by CYP2C9, CYP3A4, and CYP3A5 were 0.21, 0.34, and 0.19 μM-1∙min-1, respectively. The kcat/Km values of hydroxylation at the 1-, 2-/3-, and 4-n-butyl group in CYP2C9 were 0.0076, 0.041, and 0.035 μM-1∙min-1, respectively. The kcat and Km values provide information for the prediction of FMS metabolism in vivo. In addition, simultaneous determination of the FMS metabolites may be used to evaluate CYP2C9 and CYP3A4/5 activity.
法米沙坦（Fimasartan，FMS）是一种血管紧张素 II 受体拮抗剂，它在体内代谢为 FMS S-氧化物、FMS N-葡萄糖醛酸苷、氧化脱硫 FMS（BR-A-557）和羟丁基 FMS 等。本研究的目的是利用细胞色素 P450（CYP）和黄素单加氧酶（FMO）等重组酶，以及选择性化学抑制剂，来鉴定参与 NADPH 依赖性 FMS 代谢的酶。结果表明，CYP 而不是 FMO 在 FMS 代谢中起主要作用。CYP2C9、CYP3A4 和 CYP3A5 参与 FMS S-氧化物的形成，该产物进一步由 CYP3A4/5 代谢为 BR-A-557。CYP2C9 则专一地参与丁基羟化。CYP2C9、CYP3A4 和 CYP3A5 进行 S-氧化的特异性常数（kcat/Km）值分别为 0.21、0.34 和 0.19 μM-1∙min-1。CYP2C9 在位 1-、2-/3-和 4-丁基的羟化的 kcat/Km 值分别为 0.0076、0.041 和 0.035 μM-1∙min-1。kcat 和 Km 值为预测 FMS 体内代谢提供了信息。此外，FMS 代谢物的同时测定可用于评估 CYP2C9 和 CYP3A4/5 的活性。
