阿托伐他汀钙片在人及Beagle犬体内药动学差异的对比

Comparison on Pharmacokinetics of Atorvastatin Calcium Tablets in Human and Beagle Dogs

采用液相色谱-串联质谱法分别测定人和Beagle犬口服阿托伐他汀钙片后血浆中的阿托伐他汀(1)及其活性代谢物,包括邻位羟基化物(2)和对位羟基化物(3),计算并对比人和Beagle犬血浆中1、2、3的药动学参数。结果显示,药物在人体内主要以原型1的形式存在,检测不到代谢物3;而在Beagle犬体内主要以代谢物2的形式存在,另检测到原型药物占约30%,代谢物3约占5%。原型药物1在人体内的消除半衰期约为Beagle犬的3倍,而清除率仅约为Beagle犬的65%。可见,人与犬口服药物的药动学存在显著的种属间差异,Beagle犬对原型药物的代谢速度和程度均显著高于人体。

A LC-MS/MS method was established for the determination of atorvastatin （1） and its active metabolites, ortho-hydroxy-atorvastatin （2） and para-hydroxy-atorvastatin （3）, in human and Beagle dog plasma after oral administration of atorvastatin calcium tablets. The pharmacokinetic parameters of 1, 2 and 3 were calculated and compared. The results indicated that the parent drug 1 was the main format circulated in human bodies, and the active metabolite 3 was not detected. While in Beagle dogs, the active metabolite 2 was the main format, with co-existence of parent drug I accounting for 30 % as well as metabolite 3 accounting for 5 %. The half life time of I in human bodies was about three times as long as that in Beagle dogs, while its clearance in human bodies was about 65 % of that in Beagle dogs. In conclusion, there were significant pharmacokinetic differences of 1 between human and Beagle dogs. Both metabolism velocity and extent of parent drug in Beagle dogs were significantly higher than those in human bodies.