重组抗人血小板GPⅡb/Ⅲa嵌合单抗F(ab′)2在Beagle犬体内药动学

 目的研究了重组抗人血小板GPIIb/Ⅲa嵌合单抗F(ab′)₂经静脉单次给药后在Beagle犬中的药动学。方法按不同时间点采血,分离血浆,采用双抗体夹心酶联免疫吸附实验(ELISA)法测定犬血浆中嵌合单抗F(ab′)₂的浓度,根据非房室统计矩模型进行曲线拟合并计算药动学参数。结果Beagle犬分别静脉单次注射高、中、低(1.2,0.8,0.4mg·kg^-1)后,t_1/2分别为(7.35±0.65),(8.28±0.68)和(7.03±3.26)h,CL_s与V_ss随着剂量的减小发生增加的变化,血药浓度-时间曲线下面积AUC_0-inf分别为(2453.70±371.59),(1097.64±142.11)和(362.63±169.12)μg·h·L^-1,剂量之比为3:2:1,对应的AUC_0-inf比值为6.8:3:1,剂量与AUC成正相关性,相关系数R²=0.9714,但是AUC_0-inf的增加量大于剂量的增加量。结论在本实验的剂量范围内,剂量与AUC_0-inf成正相关性,AUC_0-inf的增加量大于剂量的增加量,预示在以上剂量范围内嵌合单抗F(ab′)₂在Beagle犬血浆中的浓度变化可能呈非线性药动学规律;动物性别对药动学参数无显著性影响。

Pharmacokinetics of Anti-GPⅡb/Ⅲa mAb [ chimeric F( ab')2 ] after an Intravenous Administration in Beagle Dogs

OBJECTIVE To evaluate the pharmacokinetics of mouse-human chimeric F(ab')₂ fragment in Beagle dogs.METHODS 12 Health Beagle dogs were divided into three groups randomly(2 male and 2 female in each group),and were treated with a single intravenous dosages of 1.2,0.8,0.4 mg·kg^-1.Chimeric F(ab')₂ respectively,chimeric F(ab')₂ in plasma of 12 Beagle dogs at different sampling time was determined by ELISA.The pharmacokinetic parameters were estimated by WinNonlin software and analyzed by SPSS statistic analysis.RESULTS The mean concentration-time curves of chimeric F(ab')₂ was fitted to noncompartment.The main pharmacokinetic parameters as follows:t_1/2(7.35±0.65),(8.28±0.68) and(7.03±3.26)h,AUC_0-inf(2 453.70 ±371.59),(1 097.64±142.11) and(362.63±169.12) μg·h·L^-1,respectively.With the decrease of dosage,CL_s and V_ss were increased.CONCLUSION AUC_0-inf are dose-dependent pharmacokinetics but not dose-proportinal over the dose range of 0.4～1.2 mg·kg^-1.There is no significant difference in the pharmacokinetics parameters between male and female dogs.