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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 investigate the in vivo pharmacokinetics and tissue distribution of paclitaxel-loaded lipid microbubbles (PLM) and the in vivo release of drugs under ultrasound irradiation. Methods Kunming mice were injected 5 mg / kg of PLM and Taxol through tail vein, and the contents of paclitaxel in plasma, liver and spleen of mice at different time points were determined by reverse-phase high performance liquid chromatography (RP-HPLC) Drug concentration. The plasma data were processed with 3P97 to give the main pharmacokinetic parameters. In vivo drug release experiments, 40 mice were divided into 4 groups: PLM group, PLM irradiation group, Taxol group, Taxol irradiation group, tail vein immediately after PLM injection, Mouse liver, RP-HPLC method for the determination of paclitaxel content in mouse liver tissue. Results The drug-time curves of mice injected with PLM and Taxol all accord with two-compartment model. The elimination half-lives (T1 / 2Ke) of PLM and Taxol were 13.060 and 5.283 h, respectively. At 48 h, the drug concentration in PLM group was significantly higher than that in Taxol group (P <0.05). Tissue distribution results showed that the drug concentration in liver and spleen of PLM group was higher than that of Taxol group at each time point (P <0.05), and the content of paclitaxel in liver of PLM-irradiated group was significantly higher The drug content in PLM group and other groups (P <0.05). Conclusion PLM can prolong the circulation time of drugs in mice to some extent and increase the distribution of reticuloendotheliod system such as liver and spleen. PLM can obviously increase the number of irradiated local Tissue drug concentration.