新型肺靶向多西他赛脂质体在原位肺癌模型兔中的药动学研究

Study on pharmacokinetics of novel lung-targeted Docetaxel liposome in in-situ lung cancer model rabbit

目的 研究新型肺靶向多西他赛脂质体(DTX-LP)在原位肺癌模型兔中的药动学行为。方法 采用超高效液相色谱-二级串联质谱(UPLC-MS/MS)法测定DTX在兔血浆中的含量,并进行方法学考察。采用胸腔微创穿刺术制备原位肺癌模型兔,然后随机分为多西他赛注射液(DTX-IN)组和DTX-LP组,耳缘静脉注射给予相应药物,给药剂量均为1.0 mg/kg(以DTX计),然后于5、15、30、60、90、120、240、480 min时取血,测定血浆中DTX浓度。采用DAS 3.3软件进行拟合与分析,并计算药动学参数。结果本研究所用UPLC-MS/MS法的准确度、精密度良好,符合生物样品分析要求。与DTX-IN组比较,DTX-LP组的药-时曲线趋势较平缓,各时间点的血药浓度更低,c_(max)、t_(1/2)、AUC_(0→480 min)、AUC_(0→∞)均显著降低(P<0.05)。结论 DTX-LP在血浆中的暴露量较DTX-IN降低,提示其能快速地从体循环中分布到肺靶器官。

OBJECTIVE To study the pharmacokinetic behavior of novel lung-targeted Docetaxel liposome(DTX-LP)in in-situ lung cancer model rabbit.METHODS The content of DTX in rabbit plasma was determined by UPLC-MS/MS,and methodology investigation was conducted.in-situ lung cancer model rabbit was made by the ultra-minimal invasive percutaneous puncture inoculation method.Model rabbits were randomly divided into Docetaxel injection(DTX-IN)group and DTX-LP group.The rabbits were given relevant medicine via ear vein at a dose of 1.0 mg/kg(calculated by DTX);blood was taken at 5,15,30,60,90,120,240 and 480 minutes to measure the concentration of DTX in plasma.DAS 3.3 software was adopted for fitting and analysis,and to calculate pharmacokinetic parameters.RESULTS UPLC-MS/MS method used in this study was accurate and precise,which met the requirements of biological sample analysis.Compared with DTX-IN group,drug concentration-time curve of DTX-LP was smoother,the blood concentration at each time point was lower,and cmax,t1/2,AUC0→480min and AUC0→∞were significantly decreased(P<0.05).CONCLUSIONS The drug exposure of DTX-LP in plasma is significantly reduced than DTX-IN,indicating it can be rapidly distributed from systemic circulation to liver target organs.