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目的:建立同时测定小鼠全血中6种CYP450探针药物,即咖啡因(CYP1A2)、甲苯磺丁脲(CYP2C)、奥美拉唑(CYP2C)、右美沙芬(CYP2D22)、氯唑沙宗(CYP2E1)和咪达唑仑(CYP3A11)的方法,并采用cocktail法快速评价药物对CYP450同工酶的影响。方法:蛋白沉淀法处理血样,离心后取上清,LC-MS/MS检测。选取地塞米松作为药酶诱导剂,对所建立的模型进行验证。结果:咖啡因、甲苯磺丁脲和氯唑沙宗的线性范围均为20～4 000 ng/ ml,咪达唑仑、奥美拉唑和右美沙芬的线性范围均为1～200 ng/ml。6种探针药物的日内及日间精密度均小于15%,方法回收率均大于90%。地塞米松表现出对小鼠CYP450有诱导作用。结论:本方法准确、灵敏、重现性好,可用于cocktail法快速评价整体动物主要CYP450亚型酶的活性。
OBJECTIVE: To establish a method for the simultaneous determination of six CYP450 probe drugs in mouse whole blood, namely, caffeine (CYP1A2), tolbutamide (CYP2C), omeprazole (CYP2C), dextromethorphan (CYP2D22) (CYP2E1) and midazolam (CYP3A11) method, and the cocktail method to quickly evaluate the effects of drugs on CYP450 isozymes. Methods: Blood samples were processed by protein precipitation, centrifuged and the supernatant was collected for detection by LC-MS / MS. Dexamethasone was selected as a chemozyme inducer, and the established model was validated. RESULTS: The linear ranges of caffeine, tolbutamide and chlorzoxazone were both 20-4000 ng / ml. The linear ranges of midazolam, omeprazole and dextromethorphan ranged from 1 to 200 ng / ml. The intra-and inter-day precision of 6 kinds of probe drugs were all less than 15%, and the recoveries of the methods were more than 90%. Dexamethasone shows an induction effect on mouse CYP450. Conclusion: The method is accurate, sensitive and reproducible. It can be used in cocktail method to rapidly evaluate the activity of major CYP450 isoforms in whole animals.