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目的:研究丙戊酸半钠肠溶片在中国健康志愿者中的单次及多次给药药动学特征。方法:12例受试者采用随机开放3×3拉丁方试验设计,进行单次及多次给药药动学研究。采用高效液相色谱法测定丙戊酸的血浆药物浓度。使用Win Nonlin软件计算药动学参数。结果:单次(250、500、1000 mg)给药后丙戊酸的主要药动学参数:Cmax分别为(20.51±3.36)、(39.01±4.06)、(63.76±6.90)mg/L;tmax分别为(3.1±1.1)、(3.7±2.9)、(3.2±1.8)h;AUClast分别为(427.9±106.0)、(805.4±171.2)、(1224.0±193.5)mg·h·L-1;AUCinf分别为(466.4±138.7)、(872.1±231.5)、(1315.9±247.3)mg·h·L-1。连续多次给药500mg后丙戊酸的主要药动学参数:Cmax(76.71±9.97)mg/L;tmax(3.2±1.2)h;AUClast(2057.0±344.0)mg·h·L-1;AUCinf(2212.9±397.1)mg·h·L-1。结论:该制剂具有肠溶效果,药物吸收的延迟时间约为1.5~1.8小时;单次250~500 mg给药后,丙戊酸的体内过程符合一级线性动力学,给药剂量大于500 mg时不符合一级线性动力学过程;连续多次500 mg给药后,活性成分丙戊酸在体内有明显累加,蓄积因子为2.70±0.24。
Objective: To study the single and multiple pharmacokinetic profiles of valproate hemi-sodium enteric-coated tablets in Chinese healthy volunteers. METHODS: Twelve subjects were randomized to receive a 3 × 3 Latin square design, and single and multiple-dose pharmacokinetic studies were performed. Plasma drug concentration of valproic acid was determined by high performance liquid chromatography. Pharmacokinetic parameters were calculated using Win Nonlin software. RESULTS: The main pharmacokinetic parameters of valproic acid were (Cmax 20.51 ± 3.36), (39.01 ± 4.06) and (63.76 ± 6.90) mg / L, respectively after administration of a single dose (250, 500 and 1000 mg) (3.1 ± 1.1), (3.7 ± 2.9) and (3.2 ± 1.8) h, respectively; AUClast was (427.9 ± 106.0), (805.4 ± 171.2) and (1224.0 ± 193.5) mg · h · L -1, respectively; AUCinf (466.4 ± 138.7), (872.1 ± 231.5) and (1315.9 ± 247.3) mg · h · L-1, respectively. The main pharmacokinetic parameters of valproic acid were as follows: Cmax (76.71 ± 9.97) mg / L, tmax (3.2 ± 1.2) h, AUClast (2057.0 ± 344.0) mg · h · L -1 and AUCinf (2212.9 ± 397.1) mg · h · L-1. CONCLUSION: The preparation has enteric effect and the delay of drug absorption is about 1.5 to 1.8 hours. After a single dose of 250 to 500 mg, the in vivo process of valproic acid conforms to the first-order linear kinetics and the dosage is more than 500 mg Time does not meet the first-order linear kinetic process; continuous multiple 500 mg administration, the active ingredient valproic acid in the body significant accumulation, the accumulation factor of 2.70 ± 0.24.