关键词: 白藜芦醇, 细胞色素酶P450, 药代动力学, “Cocktail”探针药物法, 药物相互作用

Abstract: 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-∞, Cmax of 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 Cmax of 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.

Key words: resveratrol, cytochrome P450, pharmacokinetics, cocktail probe method, drug-drug interaction