盐酸表阿霉素长循环热敏脂质体大鼠药代动力学考察  

Pharmacokinetics of epirubicin hydrochloride long-circulating thermosensitive liposomes in rat plasma

作　　者：吴燕[1] 张福成[1] 吴诚[2] 梅兴国[3] 吕万良[4] 

机构地区：[1]空军总医院药学部,北京100142 [2]第二炮兵总医院药剂科,北京100088 [3]军事医学科学院毒物药物研究所,北京100850 [4]北京大学药学院,北京100191

出　　处：《药学学报》2010年第3期365-370,共6页Acta Pharmaceutica Sinica

基　　金：国家重大科学研究计划资助项目(2007CB935801)

摘　　要：建立一种快速、灵敏的液相色谱-串联质谱法(LC-MS/MS)测定大鼠血浆中微量的盐酸表阿霉素(EPI)浓度的方法。以盐酸柔红霉素为内标,血浆样品用甲醇沉淀蛋白后进样,采用CAPCELLPAKC18色谱柱(3.0mm×50mm,3μm),甲醇-0.1%甲酸水溶液(80∶20)为流动相,以HP1200-6410QQQLC/MS型质谱仪多重监测(MRM)扫描方式检测。大鼠尾静脉注射等剂量(12mg·kg-1)的EPI溶液、普通脂质体(EPI-LIP)及长循环热敏脂质体(EPI-LTSL),采用DASver2.0软件拟合分析并求算各组药动学参数。结果血浆中EPI的线性范围为:0.01～50μg·mL-1,定量下限为0.01μg·mL1;批内和批间精密度均小于11.9%;平均萃取回收率分别为89.3%和92.1%;3组药物在大鼠体内药代动力学行为均符合三室模型,EPI-LTSL组的t1/2α、t1/2β、t1/2γ、AUC0-∞、MRT0-∞分别是EPI溶液组及EPI-LIP组的7.5、1.3、12.6、12.9、3.7倍及1.6、1.4、12.3、2.9、2.6倍,而后两组的平均清除率(CL)约为EPI-LTSL组的13.4倍。EPI-LTSL能显著提高AUC并延长药物在大鼠体内的循环时间。To develop and validate a liquid chromatography-tandem mass spectrometry （LC-MS/MS） method for the quantification of epirubicin hydrochloride （EPI） in rat plasma, daunorubicin hydrochloride was used as internal standard. The plasma samples were deproteinated with methanol, and separation was performed on a reversed-phase CAPCELL PAK C18 column （3.0 mm × 50 mm, 3 μm）. The mobile phase contained methanol-0.1% formic acid （80∶20）. Detection was carried out by multiple reaction monitoring on a HP1200-6410 QQQ LC/MS system. Different preparations of EPI solution, EPI-LIP （EPI-liposome） and EPI-LTSL （EPI-thermosenstive liposome） was administered in rats by i.v with the same dosage （12 mg·kg^-1）. The pharmacokinetic model and parameters were fitted and calculated by the DAS ver2.0 software. The calibration curve was linear in the range of 0.01-50 μg·mL^-1. The limit of quantification was 0.01 μg·mL^-1. RSDs of intra-and inter-batch precisions were all less than 11.9%. The average extract recovery was 89.3% and 92.1%, respectively. The pharmacokinetics of EPI in rats with all preparations were fitted to three compartments, which all fast distributed and slowly eliminated. The t1/2α, t1/2β, t1/2γ, AUC0-∞, and MRT0-∞ of EPI-LTSL group were 7.5, 1.3,12.6, 12.9, 3.7 times those of EPI solution group; and 1.6, 1.4, 12.3, 2.9, 2.6 times those of EPI-LIP group. Moreover, the CL of the latter two groups was about 13.4 times of the former EPI-LTSL group. EPI-LTSL can significantly improve AUC and prolong the circulation time of EPI in rat plasma.

关 键 词：盐酸表阿霉素 长循环 热敏脂质体 药代动力学 

分 类 号：R943[医药卫生—药剂学]