摘要
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.
出处
《中国临床药理学与治疗学》
CAS
CSCD
2013年第11期1205-1210,共6页
Chinese Journal of Clinical Pharmacology and Therapeutics
基金
创新平台提升项目(BM2012012)
"十二五"重大新药创制资助项目(2011ZX09401-003)