氯吡格雷单次和多次给药在大鼠体内的药动学特征

Pharmacokinetic characteristics of clopidogrel in rats after single dose and multiple doses of oral administration

目的建立并确证氯吡格雷羧酸代谢物SR26334血浆药物浓度的HPLC检测法,研究氯吡格雷单次和多次大剂量给药后在大鼠体内的药动学特征。方法 12只SD大鼠随机分成2组(单次给药组和多次给药组),单次和多次灌胃给予氯吡格雷30 mg·kg^(-1),多次给药为每天1次,共7 d。采用HPLC法测定给药后不同时间点血浆中SR26334浓度,用DAS 3.0处理经时血药浓度数据,计算主要药动学参数。结果单次给药和多次给药后SR26334血药浓度均于给药后约1 h达峰,ρ_(max)分别为(35.57±10.25)mg·L^(-1)和(54.28±10.39)mg·L^(-1);两者t_(1/2x)相近,分别为(6.88±1.54)h和(6.54±1.04)h;AUC_(0→24h)分别为(304.63±63.07)mg·h·L^(-1)和(543.81±43.27)mg·h·L^(-1);AUC_(0→∞)分别为(334.00±66.24)mg·h·L^(-1)和(594.91±46.84)mg·h·L^(-1);V_z/F分别为(0.92±0.23)L·kg^(-1)和(0.48±0.07)L·kg^(-1);CLz/F分别为(0.09±0.02)L·h^(-1)·kg^(-1)和(0.05±0.00)L·h^(-1).kg^(-1)。结论氯吡格雷单次与多次给药后的主要药动学参数AUC_(0→24h)、AUC_(0→∞)、V_z/F、CLz/F和ρ_(max)差异具有统计学意义(P<0.01,P<0.05),说明多次大剂量给药时其代谢物SR26334在体内有蓄积。

AIM To develop a HPLC method for the determination of carboxylic acid metabolite of clopidogrel in rat plasma, and study its pharmacokinetic profiles after single and multiple large dosage of oral administration. METH- ODS Twelve SD rats were divided into 2 groups which were orally administrated with single dose（ 30 mg kg-1. d-l） and multiple doses （ 30 mg kg-1 d-1, one dose per day, 7 continuous days）of clopidogrel, respectively. SR26334 concentrations in plasma were determined by HPLC method. The pharmacokinetie parameters of SR26334 were obtained with statistical analysis by DAS 3.0 software. RESULTS The main pharmaeokinetie parameters of single dose group and muhiple doses group were as follows： t1/2z were （6.88 ±1.54） h and （6.54 ± 1.04） h, tmax were （1.10±0.55） h and （1.17±0.41）h, Pm,xwere （35.57±10.25） mg L-1 and （54.28±10.39） mg L-1, AUC0-24h were （304.63± 63.07） mg h L-1 and （543.81 ±43.27） mg h L-1,AUC0-∞ were （334.00 ± 66.24） mg＇h＇L-1 and （594.91 ± 46.84） mg h L-1,VZ/F were （0.92±0.23）L kg-1 and （0.48±0.07） L kg-1, CLz/F were （0.09±0.02） L h-1 kg- 1 and （0.05 ± 0.00） L h- 1 kg- 1 , respectively. CONCLUSION The differences of the main pharmacoki- netic parameters of AUC0-24h, AUC0-∞ , Vz/F, CLz/F and Pmax between 2 groups are significant（ P 〈 0.01, P 〈 0.05）. After multiple large dosage of clopidogrel, there are drag accumulation in vivo.