胆固醇-半乳糖配体介导多烯紫杉醇脂质体大鼠体内药动学和小鼠组织分布研究

Pharmacokinetics of docetaxel liposomes modified with cholesterol-galactose ligand in rats and the tissue distribution in mice

目的:考察胆固醇-半乳糖配体介导的多烯紫杉醇脂质体大鼠体内药动学及小鼠组织分布学特征。方法:大、小鼠分别尾静脉注射多烯紫杉醇配体脂质体(docetaxel liposomes modified with galactose ligand,G-DOC-L)、多烯紫杉醇普通脂质体(docetaxel conventional liposomes,DOC-L)、多烯紫杉醇注射液(docetaxel injection,DOC-i),大鼠于不同时间点眼内眦取血,小鼠于不同时间点解剖,取组织匀浆液,建立LC-MS/MS法测定生物样品中多烯紫杉醇的浓度,运用DAS 2.0软件计算药动学参数。结果:研究结果显示,DOC-i,DOC-L,G-DOC-L血浆半衰期(t1/2z)分别为4.35,2.97和3.39 h;清除率分别为1.52,1.09,4.19 L·kg-1·h-1。小鼠组织分布,DOC-i,DOC-L,G-DOC-L肝摄取率分别为6.54%,4.06%,55.01%,肾摄取率分别为21.64%,10.74%,7.66%。结论:与DOC-i及DOC-L相比,G-DOC-L可较快在血液中消除,肝脏摄取率较高,而肾脏摄取率较低,对肝脏具有特异的靶向性。

Objective： To compare the pharmacokinetic parameters in rats and tissue distribution in mice after injection of docetaxel liposomes modified with cholesterol-galactose （G-DOC-L）, conventional liposomes （DOC-L） and docetaxel injection （DOC-i） , and investigate the pharmacokinetics of G-DOC-L injection in rats. Methods： The pharmacokinetic parameters of intravenously injected G-DOC-L were compared with those of DOC-L and DOC-i. The blood samples and tissue samples were collected at the designed time points, and DOC concentra- tions were measured by LC-MS/MS. DAS 2.0 was used to calculate the pharmacokinetics parameters. Results： The t1/2z of DOC-i, DOC-L and G-DOC-L were 4.35, 2.97 and 3.39 h; CLs were 1.52, 1.09 and 4.19L·kg^-1·h^-1 , respectively. The hepatic uptake rate was 6.54% , 4.06% and 55.01% ; renal uptake rate was 21.64% , 10.74% and 7.66% , respectively. Conclusion： G-DOC-L can remarkably reduce the blood exposure, and have high hepatic uptake rate and low renal uptake rate. Liver may be a specific target of G-DOC-L.