Combretastatin A4及其磷酸酯二钠在大鼠体内的药代动力学比较研究

Pharmacokinetics of Combretastatin A4 and Combretastatin A4 Phosphate in SD rats

目的:采用LC-MS/MS技术比较研究Combretastatin(CA4)及其磷酸酯二钠(CA4P)前药分别给药于SD大鼠后的药代动力学差异。方法:12只SD大鼠禁食后分别单次尾静脉给予50mg/kg CA4P或36mg/kg CA4(等摩尔量),采集不同时间点血样,采用LC-MS/MS方法进行血样药物浓度测定,求算相应的药代动力学参数,并建立CA4P-CA4转化的药动学模型。结果:大鼠单剂量i.v.50mg/kg CA4P或36mg/kg CA4后,CA4P和CA4血浆药物浓度-时间曲线下面积AUC0-∞分别为(27126±4142)、(7751±801)、(5037±1433)ng·h·mL-1,消除半衰期t1/2分别为(0.85±0.35)、(1.27±0.33)和(0.95±0.65)h。CA4P和CA4在SD大鼠体内药动学行为均无性别差异。结论:大鼠单剂量i.v.50mg/kg CA4P后,CA4P在体内迅速转化为CA4,相比于直接i.v.36mg/kg CA4,CA4在体内的暴露量(AUC0-∞)显著性提高(P<0.05),消除半衰期t1/2也有所增加,为前药CA4P的药代动力学优势。

AIM. An LCMS/MS method was set up for the comparative evaluation of pharma cokinetics of CA4P and CA4 in SD rats. METH ODS： 12 fasted SD rats were single intravenous administration of 50 mg/kg CA4P or 36 mg/kg CA4 （same molar amount）. Plasma samples were collected at different time points and con centrations of CA4P and CA4 were analyzed by LCMS/MS. The pharmacokinetic parameters were calculated and CA4PCA4 transformation were simulated by pharmacokinetie model. RE SULTS： After i. v. administration of 50 mg/kg CA4P or 36 mg/kg CA4, the AUCof CA4P orCA4 were （27126±4142）, （7751±801） and（5037±1433） ng. h. mL-1, respectively, the tw2 were （0.85 ±0.35 ）, （ 1.27 ±0.33 ） and （0.95±0.65） h, respectively. No gender differ ences were found in rats. CONCLUSION： The exposure of CA4 was increased significantly by soluble CA4 phosphate in SD rats. CA4P was rapidly transformed into CA4 after a single i. v. administration of CA4P in rats, according to the pharmacokinetic model of CA4PCA4 transfor mation set up by us.