基于Cocktail探针药物法分析辛伐他汀对肝脏药物代谢酶的影响

Analysis of the effect of simvastatin on drug metabolic enzymes in liver based on Cocktail probe drug assay

目的利用Cocktail探针药物法分析辛伐他汀对肝脏药物代谢酶CYP450活性的影响,为药物相互作用研究提供参考,促进临床合理用药。方法选择CYP450酶中亚型相应的特异性探针底物,UPLC-MS测定探针药物血药浓度,并使用DAS3.0软件计算药代参数。通过空白对照组和辛伐他汀组中探针底物药代参数的比较,评价辛伐他汀对CYP450酶活性的影响。结果与空白对照组比较,辛伐他汀组中非那西汀的AUC降低,甲苯磺丁脲、氯唑沙宗和睾酮的AUC升高,奥美拉唑和美托洛尔的主要药代参数与空白对照组比较均无显著性差异。结论辛伐他汀对大鼠的CYP1A2有诱导作用,对CYP2C9、CYP2E1和CYP3A4有抑制作用,而对CYP2C19和CYP2D6无显著性影响。

Objective To analyze the effect of simvastatin on the activity of CYP450 in liver by using Cocktail probe drug method,and to provide reference for drug interaction research and promote rational drug use in clinic.Methods The specific probe substrates corresponding to the subtypes of CYP450 enzyme were selected and UPLC-MS was used to determine the drug concentration of the probe drug in plasma.The pharmacokinetic parameters were calculated by DAS3.0.The effect of simvastatin on CYP450 activity was evaluated by comparing the pharmacokinetic parameters of probe substrates in blank control group and simvastatin group.Results Compared with the blank control group,the AUC of fenacetin in simvastatin group decreased,the AUC of tolbutamide,chlorzoxazone and testosterone increased,and the main pharmacokinetic parameters of omeprazole and metoprolol had no significant difference compared with the blank control group.Conclusion Simvastatin can induce the activity of CYP1 A2 in rats,inhibit the activity of CYP2 C9,CYP2 E1 and CYP3 A4,but has no significant effect on the activity of CYP2 C19 and CYP2 D6.