丙戊酸半钠肠溶片人体药动学研究

Pharmacokinetics of semisodium valproate enteric-coated tablets in healthy Chinese volunteers

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WinNonlin软件计算药动学参数。结果：单次（250、500、1000mg）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1．5～1．8h；单次250～500mg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500mg时不符合一级线性动力学过程；连续多次500mg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。

AIM. To investigate the pharmacokinetics of semisodium valproate enteric-coated tablets in healthy Chinese volunteers after singleor multiple doses. METHODS： This open and random 3 × 3 latin clinical trial involved 12 healthy volunteers. The volunteers received three single doses and then multiple doses. The concentration of valproie acid in plasma was determined by HPLC. The parameters were calculated using WinNonlin program. RESULTS：The main pharmacokinetic parameters of valproic acid after single doses （250, 500, 1 000 mg ） were as follows： Cmax were （20.51 ±3.36）, （39.01 ± 4.06）, （63.76±6.90） mg/L, respectively; tmax were （3.1±1.1）, （3.7±2.9）, （3.2±1.8）h, respectively; AUClast were （427.9 ±106.0）, （805.4±171.2）, （1224.0±193.5） mg·h· L^-1, respectively; AUCinf were （ 466.4±138.7）, （872.1± 231.5）, （1315.9± 247.3） mg·h· L^-1, respectively. The parameters of valproic acid after multiple doses （500 mg ） were 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. CONCLUSION. The preparation has the effect of enteric, and the delay time of absorption is about 1. 5- 1.8 hours. After 250-500 mg single dose administration, the pharmacokinetic results show that valproic acid exhibits first order kinetic characteristics, but the pharmacokinetic process is nonlinear after single dose administration higher than 500 mg. After 500 mg multiple doses ad- ministration, active ingredient valproic acid exists significant accumulation, and the accumulation coefficient is 2.70 ± 0.24.