以混合探针药的方法评价白藜芦醇对人体细胞色素酶P450活性的影响

Evaluation of the effects of resveratrol on the activity human cytochrome P450 through combined probe method

目的:采用混合探针法研究白藜芦醇对人细胞色素酶P450五种亚型CYP1A2、CYP2D6、CYP2C9、CYP3A4和CYP2C19的影响。方法:采用随机对照研究,将26名男性健康受试者随机分为安慰剂组和白藜芦醇组,分别予以口服安慰剂/白藜芦醇每次1 g,每日一次,连续服药14 d,再口服咖啡因、氯沙坦、奥美拉唑、右美沙芬和咪达唑仑五种探针药物,采集不同时间的血样,检测咪达唑仑、咖啡因、奥美拉唑三种探针药物的血药浓度。并收集0~8 h尿液,记录尿量,检测氯沙坦及右美沙芬的代谢速率。比较两组之间的药代动力学差异。结果:与对照组相比,白藜芦醇组CYP1A2的探针药物咖啡因AUC0-12、AUC0-∞、Cmax分别增加32.10%(P<0.001)、71.52%(P<0.001)、10.62%(P=0.004),同时T1/2也显著增加(P=0.002);CYP2C19的探针药物奥美拉唑和CYP3A4的探针药物咪达唑仑的药代动力学参数AUC0-12、AUC0-∞、T1/2和Cmax均未见显著改变(P>0.05);CYP2C9探针药物右美沙芬与其代谢产物去甲右美沙芬比率(DTM/DT)的比率增加了79.91%(P=0.003);CYP2D6探针药物氯沙坦与其代谢产物E-3174的比率(losartan/E-3174)增加了531.34%(P<0.001)。结论:白藜芦醇多次给药后,能显著抑制CYP1A2、CYP2D6和CYP2C9的酶活性,而对CYP3A4和CYP2C19的酶活性无显著影响。

AIM:To evaluate the effects of resveratrol on five human cytochrome enzyme P450 subtypes,i.e.CYP1A2,CYP2D6,CYP2C9,CYP3A4,and CYP2C19,through a combined probe method.METHODS:We conducted a randomized controlled study in which 26 healthy male volunteers were recruited and were randomized into the resveratrol group and the placebo group.Volunteers were given oral placebo/resveratrol at a dose of 1 g each time,once daily for 14 days.Then,they took five oral probe drugs,caffeine(for CYP1A2),losartan(for CYP2D6),omeprazole(for CYP2C19),dextromethorphan(for CYP2C9),and midazolam(for CYP3A4).Blood samples at different times were collected to detect the concentration of the three probes,i.e.midazolam,caffeine and omeprazole;0-8 h urine samples were collected to measure the metabolic rate of losartan and dextromethorphan.RESULTS:Compared with the placebo group,the AUC0-12,AUC0-∞,Cmaxof caffeine in the resveratrol group was increased by 32.10%(P<0.001),71.52%(P<0.001),and 10.62%,respectively(P=0.004),and T1/2 was also increased significantly(P=0.002).The AUC0-12,AUC0-∞,T1/2 and Cmaxof omeprazole or midazolam in the resveratrol group showed no significant change(P>0.05)as compared with the placebo group.The 8 h urinary DTM/DT ratio was increased by 79.91%(P=0.003)and 8 h urinary losartan/E-3174 ratio was increased by 531.34%(P<0.001).CONCLUSION:Resveratrol significantly inhibited the enzymatic activities of CYP1A2,CYP2D6 and CYP2C9 after repeated administration,but did not significantly change the enzymatic activities of CYP3A4 and CYP2C19.