基于L-OH脂质复合物的紫杉醇新型亚微乳与紫杉醇普通注射液血浆药代动力学及组织分布比较研究  

Comparative study on pharmacokinetics and tissue distribution of a novel microemulsion based on the paclitaxel/L-OH lipid complex and paclitaxel injection in cremophor

作　　者：马艳丽[1] 叶军[1] 张鹏霄[1] 夏学军[1] 刘玉玲[1] 

机构地区：[1]中国医学科学院,北京协和医学院药物研究所,北京市药物传输技术及新型制剂重点实验室,北京100050

出　　处：《药学学报》2013年第11期1698-1704,共7页Acta Pharmaceutica Sinica

基　　金：“重大新药创新”科技重大专项(2012ZX09301002-001)

摘　　要：本文以市售紫杉醇注射液为参比制剂，对基于L．OH脂质复合物为中间载体的紫杉醇新型亚微乳大鼠单剂量（5mg·kg-1）尾静脉给药的血浆药代动力学和组织分布进行比较研究。采用LC—MS／MS方法测定血药浓度，计算药代动力学参数；采用[3H]同位素标记，广泛考察各脏器在0．5、3、24和120h药物分布。结果显示，亚微乳药时曲线下面积（AUC）仅为参比制剂的42．55％，血浆清除率CL2提高2．27倍，表观分布容积屹增大3．81倍，肝、脾中的药物分布量极显著增加，峰浓度增幅高达5倍，肺部略有升高但无统计学差异，而心、肾、胃肠道、骨髓、主动脉、胸腺、胰腺、脂肪、肌肉、皮肤、精囊腺、生殖器官和脑等脏器的峰浓度均明显低于参比制剂，降幅40％～80％。由此提示，新型亚微乳使紫杉醇血液暴露量降低，血浆清除加快，分布容积增大，极易被网状内皮系统吞噬而靶向聚集于肝、脾、肺等组织，有利于降低紫杉醇的血液、心肾及胃肠毒性。The pharmacokinetics and tissue distributions of the novel paclitaxel microemulsion based on the L-OH lipid complex made in our laboratory were studied in this article with the commercial paclitaxel injection in cremophor as reference preparation by injected intravenously with single dose of 5 mg kg-1 in rats. LC-MS/MS method was used to determine the drug concentration in plasma and calculate the pharmacokinetic parameters. [3H]-paclitaxel was used to reveal the tissue distributions of different organs in 0.5 h, 3 h, 24 h and 120 h. The results indicated that the AUC of the emulsion group descended to 42.55%, with the CL z and Vz increased by 2.27 times and 3.81 times respectively. Tissue distribution results revealed that the emulsion showed a significantly increase in liver and spleen with a peak concentration up to 5 times; a slightly increase was observed in lung with no statistical differences; a significantly decrease in heart, kidney, gastrointestinal tract, bone marrow, aorta, thymus, pancreas, fat, muscle, skin, seminal vesicle, reproductive organs and brain with a drop of 40%-80%. These results indicated that paclitaxel microemulsion based on L-OH lipid complexes can remarkably reduced the blood exposure, accelerate plasma clearance rate and increase distribution volume. Thefact that paclitaxel microemulsion tended to be uptake by reticuloendothelial system （RES） contributed to the target in liver, spleen and lung, and help to reduce the toxicity in blood, heart, kidney and gastrointestinal tract.

关 键 词：紫杉醇新型亚微乳 L-OH脂质复合物 [3H]紫杉醇 LC-MS MS 

分 类 号：R969[医药卫生—药理学]