【摘要】 目的 评价叶酸修饰的斑蝥素/黄芩苷脂质体(DSPE-PEG_2k-folate-cantharidin&baicalin@lipsomes, FA-Can&Bai@Lips)在正常大鼠与荷瘤大鼠体内的药动学及组织分布差异。方法 以HepG2细胞悬液接种于大鼠右侧腋下诱导荷瘤大鼠模型，尾静脉注射FA-Can&Bai@Lips后采集不同给药时间点血浆与组织（心、肝、脾、肺、肾）,采用超高效液相色谱-串联质谱联用技术（UPLC-MS/MS）测定血浆及组织中斑蝥素和黄芩苷浓度，应用Phoenix WinNonlin软件计算药动学参数，并分析比较FA-Can&Bai@Lips在正常机体状态与荷瘤状态下的药动学和组织分布差异。结果 建立的同时测定斑蝥素与黄芩苷的UPLC-MS/MS方法线性关系良好，专属性、准确度与精密度、提取回收率与基质效应及稳定性等均符合生物样本检测要求。药动学参数表明，与正常组大鼠相比，荷瘤大鼠体内斑蝥素与黄芩苷的药时曲线下面积(area under the curve, AUC_0-t、AUC_0-∞)、平均驻留时间(mean residence time, MRT_0-t、MRT_0-∞)均显著升高（P<0.05）,分别增加了55.68%、72.50%、43.10%、45.95%和15.10%、42.54%、9.09%、10.53%;斑蝥素在荷瘤大鼠体内半衰期(half-life,t_1/2)缩短，但无显著性差异，而黄芩苷的t_1/2显著延长（P<0.05）,两者的表观分布容积（apparent volume of distribution,Vd）与清除率（clearance rate,CL）均明显降低。组织分布结果显示，斑蝥素与黄芩苷在荷瘤大鼠肝脏中浓度明显高于正常大鼠，其余组织药物浓度均显著低于正常大鼠。结论 UPLC-MS/MS法分析速度快、简单、特异、灵敏，可用于大鼠血浆及组织中斑蝥素与黄芩苷的测定，且证实荷瘤状态会对FA-Can&Bai@Lips的体内药动学及组织分布产生明显影响。更多还原

【Abstract】 OBJECTIVE To evaluate the difference of pharmacokinetics and tissue distribution of folate-modified cantharidin/baicalin liposomes（FA-Can&Bai@Lips） in normal and tumor-bearing rats. METHODS HepG2 cell suspension was inoculated into the right armpit of rat to induce tumor bearing animal models. After tail vein injection of FA-Can&Bai@Lips, plasma and tissues（heart, liver, spleen, lung and kidney） were collected at different time points. The concentrations of cantharidin and baicalin in plasma and tissues were determined by ultra high performance liquid chromatography-mass spectrometry（UPLC-MS/MS）. The pharmacokinetic parameters were calculated by Phoenix WinNonlin software, and the pharmacokinetic and tissue distribution differences of FA-Can&Bai@Lips in normal and tumor-bearing rats were analyzed and compared. RESULTS The UPLC-MS/MS method for simultaneous determination of cantharidin and baicalin has a good linear relationship. The specificity, accuracy and precision, extraction recovery rate and matrix effect, residual effect and stability meet the requirements of biological sample detection. The pharmacokinetic parameters showed that the area under the curve(AUC_0-t,AUC_0-∞), the mean residence time(MRT_0-t, MRT_0-∞) of cantharidin and baicalin in plasma of tumor-bearing rats were significantly higher than those in normal rats（P<0.05）, which increased by 55.68%, 72.50%, 43.10%, 45.95% and 15.10%, 42.54%, 9.09%, 10.53% respectively. The half-life(t_1/2) of cantharidin was slightly shortened in tumor-bearing rats with no significant difference, while the t_1/2 of baicalin was significantly prolonged（P<0.05）. The apparent volume of distribution（Vd） and clearance（CL） of cantharidin and BA were significantly decreased. The results of tissue distribution showed that the concentrations of cantharidin and BA in the liver of tumor-bearing rats were significantly higher than those of normal rats, and the other tissues were significantly lower（P<0.01）. CONCLUSION The UPLC-MS/MS method is rapid, simple, specific and sensitive, and can be used for the determination of cantharidin and baicalin in plasma and tissues of rats. It is confirmed that the tumor-bearing status can significantly affect the pharmacokinetics and tissue distribution of FA-Can&Bai@Lips in vivo.更多还原