鸡尾酒法评价阿普唑仑对大鼠CYP450酶活性的影响

To evaluate the effect of alprazolam on the activities of CYP450 enzymes in rats with a cocktail approach

目的评估阿普唑仑对CYP450酶活性能力的影响,运用鸡尾酒法评价CYP2B1、CYP2D1、CYP1A2、CYP3A2和CYP2C11酶活性。方法将大鼠随机分为对照组和阿普唑仑3组。对照组给予生理盐水,阿普唑仑3组(低、中、高)大鼠灌胃给药5 mg/kg、10 mg/kg、20 mg/kg阿普唑仑,连续给药28 d。然后第29 d灌胃给予5种探针药物,UPLCMS/MS法测定探针药物浓度。结果与对照组对比,阿普唑仑中剂量和高剂量组的安非他酮和咪达唑仑AUC_((0-t))都有降低(P<0.05)。与对照组对比,阿普唑仑组的美托洛尔、非那西丁和甲苯磺丁脲AUC_((0-t))、CL_(z/F)差异无统计学意义(P>0.05)。结论阿普唑仑不会诱导或抑制大鼠CYP2D1、CYP1A2和CYP2C11酶活性,但阿普唑仑有诱导大鼠CYP2B1和CYP3A2酶活性。

Objective To evaluate the effect of alprazolam on CYP450 enzyme activity and evaluate the CYP2 B1,CYP2 D1,CYP1 A2,CYP3 A2 and CYP2 C11 enzyme activities using a cocktail approach.Methods Rats were randomly divided into control group and alprazolam groups.The control group was given normal saline,and the rats in the three groups of alprazolam(low,medium,and high)were orally administered 5 mg/kg,10 mg/kg,and 20 mg/kg of alprazolam for 28 days.Then on the 29^(th)day,5 kinds of probe drugs were administered by gavage,and the concentration of probe drugs were detected by ultraperformance liquid chromatography-tandem mass spectrometry method.Results Compared with the control group,the AUC_(0-t)of bupropion and midazolam in the middle and high dose groups of alprazolam were reduced(P<0.05).Compared with the control group,there was no statistical significance on the difference in the AUC_(0-t)and CL_(z/F)of metoprolol,phenacetin,and tolbutamide in the alprazolam group(P>0.05).Conclusion Alprazolam does not induce or inhibit CYP2 D1,CYP1 A2 and CYP2 C11 enzyme activities in rats.But alprazolam could induce CYP2 B1 and CYP3 A2 enzyme activity in rats.