2种姜黄素聚合物胶束在大鼠体内的药动学比较研究

Comparison of pharmacokinetics of curcumin in rats administered with two kinds of polymeric micelles

研究嵌段共聚物材料m PEG-PLA疏水端经Boc-苯丙氨酸(BP)修饰后对所制备姜黄素(curcumin,CUR)聚合物胶束药动学特征的影响,为其制剂处方优化提供试验依据。将健康雄性SD大鼠随机分为3组,分别经尾静脉单次注射给予载药胶束CUR-m PEG-PLA,CUR-m PEG-PLA-BP和参比制剂CUR的DMSO溶液(n=6),给药剂量以CUR计均为20 mg·kg-1。分别于给药前和给药后不同时刻采集各组动物血样,HPLC测定CUR血药浓度,绘制药-时曲线,采用DAS 2.0软件计算非房室模型药动学参数,并进行组间差异的统计分析。结果发现,载药胶束CUR-m PEG-PLA在大鼠体内的药动学特征与CUR的DMSO溶液相似,主要药动学参数无显著性差异;但CUR-m PEG-PLA-BP组较CUR-m PEG-PLA组的药-时曲线下面积(AUC0-∞)显著提高,清除率(CL)降低,同时消除半衰期(t1/2)和平均滞留时间(MRT)明显延长(P<0.05)。研究结果表明,采用疏水端修饰的共聚物材料m PEG-PLA-BP制备的姜黄素载药胶束体内药动学特性更佳,适于深入研发。

To investigate the effect of end-capped modification of m PEG-PLA with Boc-phenylalanine（ BP） on pharmacokinetic characteristics of curcumin（ CUR） loaded micelles,and then provide experimental evidence for prescription optimization. Healthy male SD rats were randomly divided into three groups and they were intravenously administered with a single injection of CUR-m PEG-PLA micelles,CUR-m PEG-PLA-BP micelles and reference formulations DMSO solution（ n = 6）. The doses were 20 mg·kg-1in term of CUR. Blood samples were collected before and after administration,and the concentration of curcumin in blood plasma was determined by HPLC to draw time-concentration curve. Non-compartmental pharmacokinetic parameters were calculated by using DAS 2. 0 software and statistical analysis was conducted between the different groups. The results indicated that the pharmacokinetic characteristics of CUR-m PEG-PLA micelles were similar to those of the free drug of CUR dissolved in DMSO,and the main pharmacokinetic parameters had no significant difference between the two groups. However,as compared with CUR-m PEG-PLA micelles,CUR-m PEG-PLA-BP micelles had a significantly increased area under the time-concentration curve（ AUC）,significantly prolonged half-life of elimination（ tl/2）and mean residence time（ MRT）,and reduced total body clearance（ Cl）（ P〈0. 05）. In conclusion,the amphipathic block copolymer of m PEG-PLA-BP could provide curcumin loaded micelles with preferable pharmacokinetic properties in vivo,and CUR-m PEG-PLA-BP micelles were worthy of further research and development.