盐酸吡格列酮和阿托伐他汀钙在Beagle犬体内的药动学相互作用研究

Pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in Beagle dogs

探讨盐酸吡格列酮和阿托伐他汀钙在Beagle犬体内的药动学相互作用。采用自身对照随机交叉的方法。9只Beagle犬随机分成3组。第1周期3组动物分别口服阿托伐他汀钙片(A),盐酸吡格列酮片(B)和阿托伐他汀钙片+盐酸吡格列酮片(C);第2周期3组动物分别口服B、C、A;第3周期3组动物分别口服C、A、B。连续给药6天,在给药的第1天和第6天采集前肢静脉血,用LC-MS/MS法测定盐酸吡格列酮和阿托伐他汀钙的血药浓度,各周期间清洗期为7天。药物合用组与药物单独使用组的主要药动学参数用DAS 3.2.1统计矩法计算AUC0-t和Cmax用"生物等效性与生物利用度"模块下的90%可信区间法进行统计。与单独给药比较,联合使用盐酸吡格列酮和阿托伐他汀钙的主要药动学参数AUC0-t和Cmax在90%可信区间的生物等效性统计结果不合格;药物单用组与合用组的tmax用配对Wilcoxon检验,结果 P>0.05。药动学参数t1/2、CLint、MRT和V/F经t检验差异无统计学意义。Beagle犬同时服用盐酸吡格列酮和阿托伐他汀钙存在一定药动学相互影响。

The object of this study is to investigate the pharmacokinetic interaction of pioglitazone hydrochloride and atorvastatin calcium in healthy adult Beagle dogs following single and multiple oral dose administration. A randomized, cross-over study was conducted with nine healthy adult Beagle dogs assigned to three groups. Each group was arranged to take atorvastatin calcium （A）, pioglitazone hydrochloride （B）, atorvastatin calcium and pioglitazone hydrochloride （C） orally in the first period, to take B, C, A in the second period, and to take C, A, B in the third period for 6 days respectively. The blood samples were collected at the first and the sixth day after the administration, plasma drug concentrations were determined by LC-MS/MS, a one-week wash-out period was needed between each period. The pharmacokinetic parameters of drug combination group and the drug alone group were calculated by statistical moment method, calculation of Cmax and AUC0-t was done by using 90% confidence interval method of the bioequivalence and bioavailability degree module DAS 3.2.1 software statistics. Compared with the separate administration, the main pharmacokinetic parameters （Cmax and AUC0-t） of joint use of pioglitazone hydrochloride and atorvastatin calcium within 90%confidence intervals for bioequivalence statistics were unqualified, the mean tmax with standard deviation used paired Wilcoxon test resulted P 〉 0.05. There was no significant difference within tl/2, CLint, MRT, V/F. Pioglitazone hydrochloride and atorvastatin calcium had pharmacokinetic interaction in healthy adult Beagle dogs.