载药脂质微泡造影剂在小鼠体内的药代动力学及定位释放实验研究

Study on pharmacokinetics and drug-release of self-made paclitaxel-carrying liposome microbubMes

目的探讨载紫杉醇脂质微泡(PLM)的体内药代动力学,组织分布及超声辐照下药物的体内定位释放。方法采用昆明小白鼠,以5 mg／kg经尾静脉注射PLM和紫杉醇(Taxol),反相高效液相色谱法(RP-HPLC)测定不同时间点小鼠体内血浆、肝、脾组织中紫杉醇的药物浓度。血浆中的数据用3P97处理,得到各主要药代动力学参数。体内药物定位释放实验,40只小鼠分为4组,PLM组、PLM辐照组、Taxol组、Taxol辐照组,尾静脉注射PLM后即刻,采用一定声强的超声于体表定点辐照小鼠肝脏,RP-HPLC法测定小鼠肝组织中紫杉醇的含量。结果小鼠静脉注射PLM及Taxol后的药-时曲线均符合二室模型。PLM及Taxol的消除半衰期(T1／2Ke)分别为13．060 h和5．283 h。48 h时PLM组在血中的药物浓度明显高于Taxol组(P<0．05)。组织分布结果显示,各时间点PLM组在肝脾组织内的药物浓度分别高于相应时间点的Taxol组(P<0．05);PLM辐照组的小鼠肝组织内的紫杉醇含量明显高于PLM组及其余各组的药物含量(P< 0．05)。结论PLM可在一定程度上延长药物在小鼠体内的循环时间,并在肝脾等网状内皮系统的分布增加;一定声强的超声经体表定位辐照PLM后,能明显提高辐照局部组织的药物浓度。

Objective To study pharmacokinetics and tissue distribution of paclitaxel-carrying lipesome microbubbles（PLM） in vivo and explore the paclitaxel concentration in liver after PLM was destructed by ultrasound. Methods In pharmacokinetic study, blood , liver and spleen samples of mice were collected at different time ＇after PLM or Taxol were administered intravenously. The concentration of paclitaxel was deermined by reversed phase high-performance liquid chromatography （RP-HPLC） method. The data obtained from plasma were processed using 3P97 program. Forty mice were divided into 4 groups：Taxol, PLM, PLM with uhrasound,Taxol with ultrasound;Ten mice in each group. The concentration of paclitaxel in liver was determined by RP-HPLC method. Results The concentration - time curve of PLM fitted a two compartment model. The T1/2Ke of PLM was 13. 060 h and that of Taxol was 5. 283 h. The concentration of paclitaxel in plasma of PLM group at 48 h was significantly higher than that of Taxol group（ P 〈 0.05）, respectively at every corresponding time. Biodistribution studies showed that the concentrations of paclitaxel in PLM group absorbed in two major organs of the mononuclear phagocyte system - liver and spleen, were more than those of Taxol. After PLM destructed by ultrasound from body surface of mice, the concentration of paclitaxel in liver was the highest among every other groups（ P 〈 0.05 ）. Conclusion PLM has relatively longer circulating time in mice. PLM are absorbed largely in two major organs of the reticuloendothelial system. It will obviously promote PLM to release drug in target tissue after destructed by a certain ultrasound energy from body surface.