中国临床药理学与治疗学2016，Vol.21Issue(5)：533-537,547,6.
丙戊酸钠缓释片在健康人体内的药动学研究
Study on the pharmacokinetics of sodium valproate sustained-release tablets in healthy volunteers
摘要
Abstract
AIM:To establish a LC-MS/MS method for the determination of valproic acid in human plasma to investigate the pharmacokinetics of sodium valproate sustained-release tablets in healthy volunteers.METHODS:A Waters YMC C 1s column (150 mm×2.1 mm,5 μm) at a column tem-perature of 40 ℃ and a mobile phase consisting of acetonitrile-10 mmoL/L ammonium acetate (85:15,V/V) at a flow rate of 300 μL/min were used with an injection volume of 2 μL for LC.The negative ESI and MRM mode were used for triple quadrupole MS,in which the selected reaction monitoring ions were m/z 143.0→143.0 for valproic acid and m/z 469.4→425.5 for glycyrrhetic acid as the internal standard.In the randomized,crossover study,twenty four healthy male Chinese volunteers were divided into two groups and were given a single oral dose of 0.5 g sodium valproate sustained-release tablets (test or reference formulation) after an overnight fast,followed by collecting cubital venous blood samples at different time points (0-96 h).Subsequently,another twenty four volunteers were given multiple oral doses (0.5 g,qd,for 8 d) of test or reference formulation and the blood samples were collected in the same way on day 8.All the blood samples after plasma separation and extraction were determined by the established LC-MS/MS method and the pharmacokinetic parameters of valproic acid were calculated by DAS2.0 software.RESULTS:The established LC-MS/MS method was evaluated as follows:the calibration curve of valproic acid in human plasma was linear in the range of 0.087 5-89.6 μg/mL,the precision,accuracy and recovery were good,and no significant matrix effect was found.The pharmacokinetics of sodium valproate sustained-release tablets were evaluated as follows:Cmax and AUC0-96 h,the main pharmacokinetic parameters,for test formulation were (42.9 ± 14.4) μg/mL and (1 214.5 ±372.8) μg· h · mL-1 for single oral dose and (65.1 ± 31.6) μg/mL and (1 106.6 ± 484.9) μg · h · mL-1 for multiple oral doses(P ＞ 0.05,vs reference formulation).CONCLUSION:The LC-MS/MS method is proved to be specific,sensitive and accurate and it can meet the requirement for pharmacokinetic study of sodium valproate sustained-release tablets.关键词
丙戊酸钠缓释片/高效液相色谱-串联质谱法/血药浓度/药动学Key words
sodium valproate sustained-release tablet/LC-MS/MS/plasma concentration/pharmacokinetics分类
医药卫生引用本文复制引用
成舒乔,陈尧,黄卫华,谢海棠,肖坚..丙戊酸钠缓释片在健康人体内的药动学研究[J].中国临床药理学与治疗学,2016,21(5):533-537,547,6.基金项目
国家自然科学基金青年项目(81300204) （81300204）
长沙市科技计划重点项目(K1406004-31.K1308032-31) （K1406004-31.K1308032-31）
