丙戊酸半钠肠溶片人体药动学研究

中国临床药理学与治疗学 ›› 2014, Vol. 19 ›› Issue (5): 567-573.

丙戊酸半钠肠溶片人体药动学研究

刘治芳¹, 郭歆², 余鹏¹, 刘智², 程航², 阳国平³, 程泽能¹

¹中南大学药学院生物药剂学及药物代谢动力学教研室,长沙 410013,湖南;
²湖南泰格湘雅药物研究有限公司,长沙 410013,湖南;
³中南大学湘雅三医院,长沙 410013,湖南

收稿日期:2013-09-23 修回日期:2014-04-17 出版日期:2014-05-26 发布日期:2014-06-05
通讯作者: 程泽能,男,教授,博士生导师,研究方向:药物代谢及动力学研究。Tel: 0731-82063078 E-mail: chengzn@csu.edu.cn
作者简介:刘治芳,女,硕士研究生在读,研究方向:药物代谢及动力学研究。Tel: 18874215498 E-mail: csupharmacy@163.com
基金资助:
国家“重大新药创制”科技重大专项(2012ZX09303014-001)

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

LIU Zhi-fang¹, GUO Xin², YU Peng¹, LIU Zhi², CHENG Hang², YANG Guo-ping³, CHENG Ze-neng¹

¹Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China;
²Hunan Tiger Xiangya R&D Co., Ltd, Changsha 410013, Hunan, China;
³Clinical Pharmacy & pharmacology Institute, Third Xiang Ya Hospital, Central South University, Changsha 410013, Hunan, China

Received:2013-09-23 Revised:2014-04-17 Online:2014-05-26 Published:2014-06-05

摘要/Abstract

摘要： 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、1000 mg)给药后丙戊酸的主要药动学参数:C_max分别为(20.51±3.36)、(39.01±4.06)、(63.76±6.90) mg/L;t_max分别为(3.1±1.1)、(3.7±2.9)、(3.2±1.8) h;AUC_last分别为(427.9±106.0)、(805.4±171.2)、(1224.0±193.5) mg·h·L^-1;AUC_inf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 500 mg 后丙戊酸的主要药动学参数:C_max(76.71±9.97) mg/L;t_max(3.2±1.2) h;AUC_last(2057.0±344.0) mg·h·L^-1;AUC_inf(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 h;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。

关键词: 丙戊酸半钠肠溶片, 高效液相色谱法, 药动学

Abstract: AIM: To investigate the pharmacokinetics of semisodium valproate enteric-coated tablets in healthy Chinese volunteers after single or 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 valproic 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: C_max were (20.51±3.36), (39.01±4.06), (63.76±6.90) mg/L, respectively; t_max were (3.1±1.1), (3.7±2.9), (3.2±1.8) h, respectively; AUC_last were (427.9±106.0), (805.4±171.2), (1224.0±193.5) mg·h·L^-1, respectively; AUC_inf 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 C_max (76.71±9.97) mg/L, t_max(3.2±1.2) h;AUC_last (2057.0±344.0) mg·h·L^-1;AUC_inf ( 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 administration, active ingredient valproic acid exists significant accumulation, and the accumulation coefficient is 2.70 ± 0.24.

Key words: semisodium valproate enteric-coated tablet, HPLC, pharmacokinetics

中图分类号:

R969.1

刘治芳, 郭歆, 余鹏, 刘智, 程航, 阳国平, 程泽能. 丙戊酸半钠肠溶片人体药动学研究[J]. 中国临床药理学与治疗学, 2014, 19(5): 567-573.

LIU Zhi-fang, GUO Xin, YU Peng, LIU Zhi, CHENG Hang, YANG Guo-ping, CHENG Ze-neng. Pharmacokinetics of semisodium valproate enteric-coated tablets in healthy Chinese volunteers[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(5): 567-573.

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