鸡尾酒探针法评价中药塞络通对大鼠代谢酶的影响

Evaluation of effects of Chinese medicine Sailuotong on metabolic enzymes in rats by cocktail probe method

目的:为预防合并用药产生的药物相互作用,考察治疗血管性痴呆的中药复方塞络通对大鼠主要药物代谢酶的影响。方法:大鼠分别灌胃给与塞络通及组方药人参、银杏叶和西红花提取物后再给与混合了大鼠CYP1A2 (咖啡因)、CYP2C(奥美拉唑和氯沙坦)、CYP2D2 (右美沙芬)和CYP1A1/2(咪哒唑仑)探针药组成的鸡尾酒探针,测定给药后不同时间点各探针及特异代谢底物的血药浓度,通过分析探针药及其代谢物药代参数及代谢率(代谢物与探针AUC之比),评价单剂量塞络通对大鼠主要CYP450酶活性的影响。结果:与空白对照相比,塞络通单次给药后没有发现各探针药代谢率有统计学意义的改变(P> 0. 05)。但探针药咖啡因的达峰时间显著推迟,代谢物峰浓度显著升高,代谢率的指标上升了31%,与人参给药后趋势较一致。单剂量塞络通使右美沙芬代谢物AUC值显著降低,代谢率下降了37%,影响主要来自于银杏叶提取物。结论:单剂量塞络通不会显著影响大鼠主要CYP450s酶代谢活性,整方变化趋势与组方药的合并作用吻合。

AIM： To prevent drug interactions induced by the combination of drugs, the effects of Sailuotong, a traditional Chinese medicine com- pound used to treat vascular dementia, on main drug metabolic enzymes in rats were investigated. METHODS ： After intragastric administration, the rats were given Sailuotong, and extract of ginseng, ginkgo leaf and crocus. They were then given cocktail of CYP1A2 （ caffeine ） , CYP2C （ omeprazole and losartan ） , CYP2D2 （ dextromethorphan ） and CYP1A1/2 （ midazolam ） probes. The blood drug concentration of each probe and specific metabolic substrate at different time points after administration was measured. The effects of single dose Sailuotong on the main CYP450 activity of rats were evaluated by analyzing the pharmacokinetic parameters and metabolic rate of the probe drug and its metabolite （ the ratio of the metabolite to the probe AUC）. RE- SULTS：Compared with the blank control, no statistically significant changes in the metabolic rate ofeach probe were found after single administration of Sailuotong （ P 〉 0.05 ）. The peak time of caffeine probe drug was significantly delayed, while the peak concentration of metabolites was significantly increased, and the metabolic rate was increased by 31%, which was consistent with the trend after administrating ginseng extract. The AUC value of dextromethorphan metabolite was significantly decreased by single dose Sailuotong, while the metabolic rate was decreased by 37% , which was mainly induced by ginkgo leaf extract. CONCLUSION： Main metabolic activity of CYP450s in rats was not significantly affected by single dose of Sailuotong. The whole change trend was consistent with the combined effect of compound prescription.