【作者】 丁莉坤； 宋颖； 杨林； 杨静； 李雪晴； 杭太俊； 宋敏； 文爱东；

【Author】 DING Li-kun, SONG Ying,YANG Lin, YANG Jing,LI Xue-qing,HANG Tai-jun, SONG Ming, WEN Ai-dong (Department of pharmacy, First Affiliated Hospital of the Fourth Military Medical University, Xi’an, Shaanxi China, 710032; Department of Pharmaceutical Analysis China Pharmaceutical University,Nanjing Jiangsu 210009)

【机构】 中国人民解放军第四军医大学第一附属医院药剂科； 中国药科大学药物分析教研室；

【摘要】 目的:建立测定人血浆中达沙替尼浓度的LC-MS-MS测定方法,并评价达沙替尼的药动学特征及2种制剂的人体生物等效性比较。方法:24名男性健康受试者随机分成2组,分别交叉给予受试制剂和参比制剂各100mg,采用LC-MS-MS测定达沙替尼的浓度,色谱柱为Thermo BDS HYPERSIL C18(250mm4.6mm,5m),流动相为甲醇-0.2%醋酸铵溶液=72:28(v/v),质谱采用MRM模式,检测离子达沙替尼488→401,伊马替尼494→394,估算达沙替尼的药动学参数及2种制剂的人体生物等效性。结果:人血浆中达沙替尼的最低定量限为1.0ng·ml-1,在1-300ng·ml-1范围内线性关系良好,批内及批间精密度RSD均小于15%。受试制剂与参比制剂的各主要药动学参数:tmax分别为(0.6±0.1)h和(0.7±0.2)h,cmax分别为(204.2±60.6)ng·ml-1和(180.6±56.3)ng·ml-1,t1/2分别为(5.48±1.4)h和(5.20±0.8)h,用梯形法计算AUC(0-48h)分别为(667.8206.9)ng·h·ml-1和(591.1165.8)ng·h·ml-1。结论:通过建立的测定方法,对主要药动学参数进行比较,评价结果显示两种制剂生物等效。更多还原

【Abstract】 Objective To establish a LC-MS-MS method for the determination of dasatinib in human plasma and to evaluate the pharmacokinetics and bioequivalence of dasatinib in healthy volunteers. Methods A 100 mg dose of the reference or test tablet was given to 24 healthy male volunteers in a randomized two-way crossover design and the plasma concentration of the drug was assayed by LC-MS-MS. Chromatographic separation was carried on a Thermo BDS HYPERSIL C 18 (250 mm 4.6 mm, 5 m) column (4.6×150 mm,5μm), with a mobile phase consisting of methanol – 0.2% ammonium acetate (72:28, v/v). Detection and quantification were performed by mass spectrometry in the multiple reaction monitoring mode with positive electrospray ionizationz at 488→401 for dasatinib, and 494→394 for IS (internal standard), respectively. The main pharmacokinetic parameters and bioequivalence of the two formulations were evaluated.Results The LOQ of the method for dasatinib in plasma was 1.0 and the calibration curve was linear over the range of 1.0-300 ng·ml -1 . The intra- and inter-run standard deviation was less than 15%.The major pharmacokinetic parameters were as follows: t max (0.6±0.1) h and (0.7±0.2) h, c max (204.2±60.6) ng·ml -1 and (180.6±56.3) ng·ml -1 , t 1/2 (5.48±1.4) h and (5.20±0.8) h, AUC (0-48 h) (667.8 206.9) ng·h·ml -1 and (591.1 165.8) ng·h·ml -1 , respectively. Conclusion The method was successful applied to pharmacokinetic study. The two formulations were bioequivalent.更多还原