UPLC-MS/MS测定地西泮对大鼠CYP450酶活力的影响

目的 基于UPLC-MS/MS同时测定大鼠血浆中的5种探针药物（安非他酮、美托洛尔、咪达唑仑、非那西丁和甲苯磺丁脲），5种探针药物分别是细胞色素P450同工酶CYP2B6，CYP2D6，CYP3A4，CYP1A2和CYP2C9底物，评价地西泮对大鼠细胞色素P450酶活性影响。方法 将大鼠随机分成地西泮低剂量组（1 mg·kg^-1）、高剂量组（5 mg·kg^-1）和对照组。地西泮低剂量组、高剂量组腹腔注射地西泮10 d，对照组腹腔注射生理盐水10 d。5种探针药物通过灌胃给予大鼠，用UPLC-MS/MS测定血浆药物浓度。结果 与对照组相比，地西泮组安非他酮、美托洛尔和非那西丁药动学参数均有统计差异。地西泮组安非他酮、非那西丁的AUC比对照组高，但美托洛尔AUC比对照组低。结论 地西泮可能会抑制大鼠CYP2B6酶活性，抑制CYP1A2酶活性，诱导大鼠CYP2D6酶活性，而对大鼠CYP3A4、CYP2C9酶活性无影响。

Effect of Diazepam on CYP450 Activity in Rats Determined by UPLC-MS/MS

OBJECTIVE To simultaneous determine bupropion, metroprolol, midazolam, phenacetin and tolbutamide in rat plasma by UPLC-MS/MS, which are the five probe drugs of the five cytochrome P450 (CYP450) isozymes (CYP2B6, CYP2D6, CYP3A4, CYP1A2 and CYP2C9), to evaluate the effect of diazepam on rat CYP450 enzyme activity. METHODS The rats were randomly divided into diazepam low dose group (1 mg·kg^-1), diazepam high dose group (5 mg·kg^-1), and control group. The rats in diazepam group were given 1 and 5 mg·kg^-1 diazepam by intraperitoneal administration for 10 d, control group was given saline solution by intraperitoneal administration for 10 d. Five probe drugs were administered to rats by gavage and plasma drug concentrations were determined by UPLC-MS/MS. RESULTS Compared with control group, there was statistical pharmacokinetic difference for bupropion, metroprolol and phenacetin in diazepam group. In diazepam group, AUC of bupropion and phenacetin were higher than that in the control group, but AUC of metroprolol was lower than that in the control group. CONCLUSION Diazepam may slightly inhibit CYP2B6 enzyme activity, may inhibit CYP1A2 enzyme activity, may induce CYP2D6 enzyme activity, but has no effect on CYP3A4, CYP2C9 enzyme activity in rats.