多西紫杉醇纳米胶束在小鼠体内的药代动力学及其肿瘤组织分布  

Pharmacokinetics and Tumor Tissue Distribution of Docetaxel Nanomicelles in Mice

作　　者：王杰[1] 王亚杰 郝单丽 臧琛[1] 易红[1] 德格晶 陈燕军[1] WANG Jie;WANG Ya-jie;HAO Dan-li;ZANG Chen;YI Hong;DE Ge-jing;CHEN Yan-jun(Institute of Chinese Materia Medica,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]中国中医科学院中药研究所,北京100700

出　　处：《中国实验方剂学杂志》2019年第7期140-145,共6页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：国家重点基础研究发展计划(973计划)项目(2014CB543003)

摘　　要：目的:探究多西紫杉醇纳米胶束的药代动力学及其在肿瘤组织中的分布情况。方法:采用薄膜水化法制备多西紫杉醇纳米胶束;利用HPLC建立多西紫杉醇(DTX)在生物样品中的含量测定方法并进行相应的方法学评价;建立小鼠Lewis肺癌模型,利用尾静脉注射给药方式分别考察游离药物(DTX),非pH敏感性载药胶束(PELA-DTX),pH敏感性载药胶束(PBAE-DTX)在给药剂量为20 mg·kg^(-1)时,对荷瘤小鼠药代动力学及组织分布的影响。结果:成功制备了多西紫杉醇纳米胶束PELA-DTX与PBAE-DTX;采用HPLC建立了多西紫杉醇在小鼠体内的含量测定方法,且该方法的线性关系、精密度、回收率均符合要求。PBAE-DTX的血药浓度在24 h内一直处于较高的水平。与PELA-DTX,DTX相比,PBAE-DTX的药时曲线下面积(AUC_(0-∞))分别增大3. 63%,8. 96%,平均驻留时间(MRT)分别延长了2. 86%和6. 43%,半衰期延长,药物血液循环时间延长。给药后1 h内,3种多西紫杉醇制剂在心、肝、脾、肺、肾及肿瘤组织中均有分布,随时间延长,分布降低,且24 h时PBAE-DTX在肿瘤组织中的分布显著高于PELA-DTX和DTX。结论:PBAE-DTX能够延长多西紫杉醇在血液中的循环时间,提高其生物利用度及在肿瘤组织的分布程度。Objective:To investigate the pharmacokinetics and the distribution in tumor tissues of docetaxel nanomicelles.Method:The docetaxel nanomicelles was prepared by filming-rehydration method.HPLC was employed to determine the content of docetaxel in biological samples and the corresponding methodological evaluation was carried out.The mouse Lewis lung carcinoma model was established,when dosage of administration in tail vein was 20 mg·kg^-1,and then the effect of free drug(DTX),non-pH-sensitive drug-loaded micelles(PELA-DTX)and pH-sensitive drug-loaded micelles(PBAE-DTX)on the pharmacokinetics and tissue distribution of tumor-bearing mice were investigated.Result:The docetaxel nanomicelles(PELA-DTX and PBAE-DTX)were successfully prepared.The method for the determination of docetaxel in mice was established by HPLC,the linearity,precision of the method and the recovery rate of samples all met the requirements.In the pharmacokinetic study,the plasma concentration of PBAE-DTX was always at a high level within 24 h.Compared with PELA-DTX and DTX,the areas under the curve(AUC0-∞)of PBAE-DTX were increased by 3.63% and8.96%,the mean residence times(MRT)were extended by 2.86% and 6.43%,the half-life and the drug blood circulation time were prolonged.In the tissue distribution study,it was found that three docetaxel preparations were distributed in the heart,liver,spleen,lung,kidney and tumor tissue within 1 h after administration,but the distribution of these drugs in the tissues was reduced along with the extension of time,the accumulation of PBAE-DTX in tumor tissue was significantly higher than that in DTX and PELA-DTX at 24 h.Conclusion:PBAE-DTX can prolong the circulation time of docetaxel in the blood,increase its bioavailability,and significantly increase its distribution in tumor tissue.

关 键 词：多西紫杉醇 pH敏感性载药胶束 药代动力学 组织分布 紫杉醇 肿瘤组织 尾静脉注射 

分 类 号：R22[医药卫生—中医基础理论] R283.6[医药卫生—中医学]