混合探针法评价天龙通心方对大鼠代谢酶活性的影响

Evaluation of Effects of Tianlong Tongxin Prescription on Metabolic Enzymes by Mixed Probe in Rats

目的为预防药物相互作用导致的临床合并用药隐患,初步探讨复方天龙通心方对大鼠体内药物代谢酶的影响。方法实验大鼠随机分为空白对照组和天龙通心组,连续灌胃给药14 d后再给予CYP1A2(咖啡因)、CYP2C6(氯沙坦)、CYP2C11(奥美拉唑)、CYP2D2(右美沙芬)和CYP3A1/2(咪达唑仑)混合探针药,检测给药后不同时间点各探针药及其特异代谢底物的血药浓度,通过比较各探针药与代谢物药代动力学参数及代谢率(AUCmetablite/AUCprobe)变化,评价连续给予天龙通心方对大鼠体内CYP450代谢酶活性的影响。结果与空白对照组比较,连续给予大鼠天龙通心方后奥美拉唑峰浓度、体内暴露量均显著下降,代谢率明显升高,差异有统计学意义(P<0.05);探针药咖啡因达峰时间显著推迟,代谢物和探针药AUC之比(AUCratio)下降30%,但差异无统计学意义(P>0.05);咪哒唑仑及代谢产物1-羟基咪达唑仑达峰时间均延迟,而峰浓度、体内暴露水平均显著下降,原型药咪哒唑仑清除率显著升高。其他各组探针底物及其代谢产物主要药代动力学参数及代谢率差异均无统计学意义(P>0.05)。结论重复给予复方天龙通心方对大鼠体内CYP2C11(人体CYP2C19)可能存在一定的诱导作用,而对CYP1A2、CYP2C6、CYP2D2和CYP3A1/2无显著影响,初步提示临床应用天龙通心方时应避免与经CYP2C19代谢的药物合并使用。

Objective To prevent potential clinical complications caused by medicine interaction through preliminarily investigating the effects of Tianlong Tongxin Prescription on metabolic enzymes in rats.Methods The experiment rats was randomly divided into blank group and Tianlong Tongxing roup.After pretreatment for 14 days with Tianlong Tongxin Prescription,these rats were given mixed probe drugs of CYP1A2(caffeine),CYP2C11(omeprazole),CYP2C6(losartan),CYP2D2(dextromethorphan)and CYP3A1/2(midazolam).The blood concentration of each probe drug and its specific metabolic substrate at different time points after administration were detected.The effects of Tianlong Tongxin Prescription on CYP450 metabolic enzyme activity in rats were evaluated by comparing the plasma pharmacokinetic parameters and metabolic rate(AUCmetablite/AUCprobe)changes of each probe drug and metabolite.Results Compared with blank group,the peak concentration and systematic exposure of omeprazole decreased significantly and the metabolic rate increased significantly after continuous administration of Tianlong Tongxin Prescription,with statistical significance(P<0.05).At the same time,the peak time of probe drug caffeine was significantly delayed,and the AUCratio of metabolites and probe drug decreased by 30%,without statistical significance(P>0.05).However,the peak time of midazolam and the metabolite 1-hydroxymidazolam were delayed,while the peak concentration and exposure levels in the body decreased significantly,and the clearance rate of the prototype drug midazolam increased significantly.The main pharmacokinetic parameters and metabolic rates of probe substrates and their metabolites in other groups were not significantly different.Conclusion Repeated administration of Tianlong Tongxin Prescription may induce CYP2C11 in rats(CYP2C19 in human),but has no significant effect on CYP1A2,CYP2C6,CYP2D2 and CYP3A1/2.It is preliminarily suggested that the combination with drugs metabolized by CYP2C19 should be avoided in clinical application of Tianlong Tongxin Prescription.