齐墩果酸对健康人体CYP1A2，CYP2E1及CYP3A4抑制作用的研究

Effect of Oleanolic Acid on CYP1A2,CYP2E1 and CYP3A4 Activity in Healthy Subjects

目的在人体内研究齐墩果酸对CYP1A2,CYP2E1及CYP3A4酶活性的影响,以预测齐墩果酸与常用临床药物的相互作用。方法分别以咖啡因、氯唑沙宗和咪哒唑仑作为CYP1A2,CYP2E1及CYP3A4的探药,采用随机、开放、双周期交叉设计,12名健康男性受试者在服用7d齐墩果酸前后均服用100mg咖啡因、400mg氯唑沙宗和7·5mg咪哒唑仑,服探药后采血测定探药及相应代谢产物的浓度,并计算相关参数。探药和代谢物的浓度分别用RP-HPLC和HPLC-MS测定。结果服用齐墩果酸7d后,咖啡因的代谢受到显著的抑制,其达峰时间、消除半衰期及药-时曲线下面积显著增加;氯唑沙宗的代谢受到轻微抑制,达峰浓度、达峰时间、消除半衰期及药-时曲线下面积均有升高趋势,但无显著性差异;咪哒唑仑的代谢未受影响。结论服用7d齐墩果酸对CYP1A2体内活性有显著抑制作用,对CYP2E1体内活性有轻微抑制作用,而对CYP3A4酶活性无影响。

OBJECTIVE To evaluate the effect of oleanolic acid on CYP1A2, CYP2E1 and CYP3A4 activity in healthy volunteers and to forecast the drug-drug interaction. METHODS A randomized, open-label, two-way crossover study was carried out. Subjects were divided randomly into either oleanolic acid tablets treatment group or group, when they were given 100 mg caffeine,400 mg chlorzoxazone and 7.5 mg midazolam before and after Oleanolic aicd administration, blood samples were collected. Plasma concentra- tions of probe drugs and their metabolites were determined by RP-HPLC or HPLC-MS. CYP1A2,CYP2E1 and CYP3A4 activity and pharmacokinetic parameters of probe drugs were compared before and after 7 days oleanolic aicd administration, RESULTS The metabolism of caffeine was inhibited significantly by oleanolic aicd , because there were markly increase in the tmax ,t1/2 and AUC of caffeine after 7 days oleanolic aicd administration. But the metabolism of chlorzoxazone was inhibited slightly, the tmax, ρmax, t1/2and AUC of chlorzoxazone were increased, without significant difference. No influences were observed on midazolam metabolism. CONCILUSION Oleanolic aicd once daily for 7 day can inhibit CYP1 A2 activity significantly , but it has little inhibition on CYP2E1 activity and no effect on CYP3A4.