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应用重组人源CYP同工酶研究参与罗通定代谢的肝药酶亚型并鉴定相关代谢产物。重组人源CYP同工酶CYP1A2、2C9、2C19、2D6和3A4与1μmol·L-1罗通定孵育后,应用LC-MS法测定孵育液中原形药物的剩余量。结果表明,CYP2C19、3A4和2D6参与罗通定的代谢转化,用整体归一化法评估各酶对罗通定代谢的贡献,分别为31.46%、60.37%和8.17%。应用LC-MSD和LC/Q-TOF-MSMS鉴定重组酶温孵样品中的代谢产物,罗通定在体外重组人源CYP温孵体系中的主要代谢途径为O-去甲基化,可生成4个O-单去甲基化的同分异构体以及1个双去甲基化产物,但CYP2C19、3A4和2D6介导罗通定O-去甲基化的位点有所不同。应用LC/Q-TOF-MSMS和LC/iTrap-MSn探讨了罗通定及其代谢产物的ESI质谱裂解规律。
Recombinant human CYP isoenzymes were used to study hepatic drug subtypes involved in lovastatin metabolism and to identify related metabolites. After the recombinant human CYP isozymes CYP1A2, 2C9, 2C19, 2D6 and 3A4 were incubated with 1 μmol·L-1 Rotundine, the remaining amount of the prototype drug in the incubation solution was determined by LC-MS. The results showed that CYP2C19, 3A4 and 2D6 were involved in the metabolic transformation of lootidine. The contribution of each enzyme to lootintine metabolism was assessed by global normalization method, which were 31.46%, 60.37% and 8.17% respectively. The metabolites of the recombinant enzyme incubated in the sample were identified by LC-MSD and LC / Q-TOF-MSMS. The main metabolic pathway of Rotundine in the in vitro recombinant human CYP incubation system is O-demethylation, which can generate 4 O-monodemethylated isomers and 1 double demethylation product, but CYP2C19, 3A4 and 2D6 mediate a different site of Rotenidine O-demethylation. The ESI mass spectrometry cleavage of lootidine and its metabolites was investigated by LC / Q-TOF-MSMS and LC / iTrap-MSn.