丹参-红花药对配伍前后对大鼠肝药酶亚型CYP1A2、CYP2E1和CYP3A4活性的影响

摘要

Objective To study the influence of Salviae Miltiorrhizae Radix et Rhizome (SMR) and Carthami Flos (CF) before and after compatibility on activitis of cytochrome P 1A2 (CYP1A2),cytochrome P2E1 (CYP2E1),and cytochrome P3A4 (CYP3A4) from rat liver microsomes.Methods Using caffeine,chlorzoxazone,and midazolam as the probe drugs ofCYP1A2,CYP2E1,and CYP3A4,the SD rats were randomized divided into four groups:control group,SMR (1.2 g crude drug/kg) group,CF (0.4 g crude drug/kg) group,and SMR (1.2 g crude drug/kg) + CF (0.4 g crude drug/kg) group.According to the above dose,rats were ig given drugs for 7 d.Rats were injected with caffeine,chlorzoxazone,and midazolam solution in tail vein 30 rain after the last administration,and the blood was collected at different time points.Metronidazole as internal standard,method has been established to determine the levels of caffeine,chlorzoxazone,and midazolam to evaluate the activities of CYP1A2,CYP2E1,and CYP3A4 by HPLC.Results Compared with control group,SMR increased the clearance rates (CL) of caffeine,chlorzoxazone,and midazolam,reduced the AUC,and t1/2 was also show a decreasing trend,but the difference was not significant.In CF group,CL of caffeine and chlorzoxazone was decreased,but the difference is not significant.CL of midazolam significantly decreased (P ＜ 0.01).AUC of chlorzoxazone increased,but the difference was not significant.AUC of caffeine and midazolam increased significantly (P ＜ 0.05 and 0.01).In SMR + CF group,the CL of caffeine and chlorzoxazone decreased significantly (P ＜ 0.05),the AUC of caffeine and chlorzoxazone increased significantly (P ＜ 0.05),and t1/2 also showed a decreasing trend,but the difference is not significant.Conclusion Compatibility of SMR and CF has an inhibitive effect on CYP1A2 and CYP2E1 in rats,and it could be one of the mechanisms of"interactive synergy".%目的 研究丹参、红花药对配伍前后对大鼠肝药酶亚型CYP1A2、CYP2E1和CYP3A4活性的影响.方法 分别选用咖啡因、氯唑沙宗和咪达唑仑作为CYP1A2、CYP2E1和CYP3A4的探针药物.将大鼠随机分为4组,即空白对照组、丹参(1.2 g生药/kg)组、红花(0.4 g生药/kg)组、丹参(1.2g生药/kg)+红花(0.4 g生药/kg)组,按上述剂量ig给药7d.于末次给药后30 min,尾iv探针药物咖啡因、氯唑沙宗和咪达唑仑溶液,在不同的时间点取血进行检测;以甲硝唑为内标,采用HPLC法检测探针药物咖啡因、氯唑沙宗和咪达唑仑的量,评价各药物组对大鼠CYP3A4、CYP2E1和CYP1A2活性的影响.结果 与空白对照组比较,丹参组咖啡因、氯唑沙宗和咪达唑仑的清除率(CL)有所增强,曲线下面积(AUC)减少,其半衰期(t1/2)有减少趋势,但差异均不显著;红花组咖啡因和氯唑沙宗的CL有所降低,但差异不显著,咪达唑仑的CL显著降低(P＜0.01),氯唑沙宗的AUC增加,但差异不显著,咖啡因和咪达唑仑的AUC明显增加(P＜0.05、0.01);丹参+红花组咖啡因和氯唑沙宗的CL明显降低(P＜0.05),曲线下面积(AUC)明显增加(P＜0.05),其t1/2有延长趋势,但差异不显著.结论 丹参、红花配伍后对CYP450亚型CYP1A2和CYP2E1有抑制作用,这可能是丹参、红花配伍协同增效的作用机制之一.