丁苯酞与阿托伐他汀钙在大鼠体内的药动力学及安全性研究

Pharmacokinetics and safety of butylphthalide and atorvastatin calcium in rats

目的明确在大鼠体内阿托伐他汀钙对丁苯酞的药动力学及两药联用对大鼠肝功能的影响。方法将14只健康SD大鼠分为单用丁苯酞(NBP组)和联合用药组(NBP+ATF组),给药7 d,并在第7天给药后不同时间点采集血液。用LC-MS/MS法测定丁苯酞的血药浓度,计算药动学参数;测定血清中的肝功能相关指标(ALT、AST、TBIL和DBIL),进行统计分析。结果NBP组丁苯酞AUC_(0-t)、t_(1/2)、CL明显低于NBP+ATF组(P<0.05),其他药动力学参数变化差异无统计学意义(P>0.05)。2组大鼠肝功能指标变化差异无统计学意义(P>0.05)。结论大鼠体内阿托伐他汀钙使丁苯酞消除速率减慢、暴露量增多、作用时间延长,在临床联合使用时,应考虑调整两药的给药剂量,同时两药联用与单用丁苯酞后肝功能指标变化差异无统计学意义。

Objective To study the pharmacokinetics of atorvastatin calcium and butylphthalide and the combination of two drugs on liver function in rats.Methods 14 SD rats(male and female)were divided into two groups.NBP group was administered intragastrically with butylphthalide,and the NBP+ATF group was administered intragastrically with butylphthalide and atorvastatin calcium for 7 days.The blood were collected at different time points on the 7th day.The blood concentration of butylphthalide was measured by LC-MS/MS method,and the pharmacokinetic parameters were calculated.The liver function related indexes(ALT,AST,TBIL and DBIL)in serum were measured and the statistical analysis was performed.Results The butylphthalide AUC _(0-t),t_(1/2) and CL of the single-drug group were significantly lower than those of the combination group and there were significant differences(P<0.05).There was no statistical difference in the changes of other pharmacokinetic parameters(P>0.05).There was no statistical difference in the changes of liver function indexes between the two groups(P>0.05).Conclusion Atorvastatin calcium can slow down the elimination rate of butylphthalide,increase the exposure dose and prolong the duration of action in rats.The dosage of atorvastatin calcium and butylphthalide should be adjusted when they are used together in clinic.At the same time,there was no significant difference in liver function between the two groups.