口服脂溶性苯磷硫胺片与水溶性盐酸硫胺素片的生物利用度评价

中国临床药理学与治疗学 ›› 2013, Vol. 18 ›› Issue (12): 1375-1382.

口服脂溶性苯磷硫胺片与水溶性盐酸硫胺素片的生物利用度评价

罗茜¹, 蔡凝芳², 郭歆³, 余鹏¹, 刘智³, 郑丽云¹, 程泽能¹

¹湖南省长沙市中南大学药学院生物药剂教研室,长沙 410013,湖南;
²漳州市医院药学部,漳州 363000,福建;
³湖南泰格湘雅药物研究有限公司,长沙 410013,湖南

收稿日期:2013-01-02 修回日期:2013-11-26 出版日期:2013-12-26 发布日期:2014-01-04
通讯作者: 程泽能,男,教授,博士生导师,研究方向:生物药剂学与药代动力学。Tel: 0731-82063078 E-mail: chengzn@csu.edu.cn
作者简介:罗茜,男,博士研究生,研究方向:生物药剂学与药代动力学。Tel: 18259675335 E-mail: Luoxi2999@163.com

Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamine hydrochloride after oral administration

LUO Xi¹, CAI Ning-fang², GUO Xin³, YU Peng¹, LIU Zhi³, ZHENG Li-yun¹, CHENG Ze-neng¹

¹The Research Institute of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Central South University, Changsha 410013,Hunan, China;
²Department of pharmacy, Zhangzhou municipal hospital of fujian province, Zhangzhou 363000, Fujian, China;
³Hunan Tiger Xiangya R&D Co., Ltd, Changsha 410013, Hunan, China

Received:2013-01-02 Revised:2013-11-26 Online:2013-12-26 Published:2014-01-04

摘要/Abstract

摘要： 目的: 比较口服脂溶性苯磷硫胺片与水溶性盐酸硫胺素片的生物利用度。方法: 20名健康男性志愿者采用2×2交叉试验设计,分别单次给予 300 mg 苯磷硫胺片和 220 mg 盐酸硫胺片。给药后于不同时间点采集肘静脉血并收集 24 h 内的尿液。采用HPLC-Flu法测定血浆及红细胞中硫胺素及二磷酸硫胺素浓度。药动学参数采用WinNonlin软件计算,同时计算马尿酸各时间段的平均排泄速率。结果: 服用苯磷硫胺片和盐酸硫胺片后血浆中硫胺素的t_1/2分别为(2.5±0.2)、(2.0±0.8) h;AUC_0-24分别为(1763.1±432.7)、(182.0±93.8) μg·h·L^-1;AUC_0-∞分别为(1837.3±466.5)、(195.8±96.6) μg·h·L^-1;C_max分别为(568.3±122.0)、(70.5±46.2) μg/L;CL/F分别为(172.3±39.2)、(1831.7±705.0) L/h;Vd/F分别为(627.9±131.8)、(5419.1±3586.6) L。红细胞中二磷酸硫胺素的AUC_0-24分别为(3212.4±740.7)、(881.8±316.2) μg·h·L^-1。与盐酸硫胺相比,苯磷硫胺片中硫胺素的相对生物利用度F为(1147.3±490.3)%,二磷酸硫胺素的相对生物利用度F为(392.1±114.8)%。服用苯磷硫胺后0~4 h 时间段尿液中马尿酸的排泄速率较盐酸硫胺组有明显加快。结论: 苯磷硫胺吸收迅速,相对生物利用度大于盐酸硫胺,给药后在 4 h 内全部转化为硫胺素。

关键词: 苯磷硫胺片, 硫胺素片, 二磷酸硫胺素, 生物利用度

Abstract: AIM: To study the bioavailability of the lipophilic benfotiamine as compared to a water-soluble thiamine hydrochloride after oral administration.METHODS: A randomized, crossover study involving 20 healthy male volunteers was carried. Each subject was given 300 mg benfotiamine or 220 mg thiamine hydrochloride. Blood samples were collected at different times and 24 h urine samples were collected after administration. The concentrations of thiamine and thiamine diphosphat in plasma or erythrocyte were determined by HPLC-Flu.The main pharmacokinetic parameters were calculated using WinNonlin program and the mean excretion rate of hippuric acid in urine was also evaluated.RESULTS: The main pharmacokinetic parameters of thiamine in plasma after taking benfotiamine and thiamine hydrochloride were as follows: t_1/2 were (2.5±0.2) and (2.0±0.8) h, respectively; AUC_0-24 were (1763.1±432.7) and (182.0±93.8) μg·h·L^-1, respectively; AUC_0-∞ were (1837.3±466.5) and (195.8±96.6) μg·h·L^-1, respectively; C_max were (568.3±122.0) and (70.5±46.2) μg/L, respectively; CL/F were (172.3±39.2)and (1831.7±705.0) L/h, respectively; V_d/F were (627.9±131.8) and (5419.1±3586.6)L, respectively. The AUC_0-24 of thiamine diphosphat in erythrocyte after taking benfotiamine and thiamine hydrochloride was (3212.4±740.7) and (881.8±316.2) μg·h·L^-1, respectively. In comparison with thiamine hydrochloride, the relative bioavailability of thiamine and thiamine diphosphat in benfotiamine were (1147.3±490.3)% and (392.1±114.8)%, respectively. The excretion rate of hippuric acid in urine in 4 h after taking benfotiamine was significantly accelerated than that after taking thiamine hydrochloride.CONCLUSION: Benfotiamine is absorbed quickly, and has better bioavailability than thiamine hydrochloride. It can be transformed to thiamine in 4 h after administration.

Key words: Benfotiamine, Thiamine, Thiamine diphosphat, Bioavailability

中图分类号:

R969.1

罗茜, 蔡凝芳, 郭歆, 余鹏, 刘智, 郑丽云, 程泽能. 口服脂溶性苯磷硫胺片与水溶性盐酸硫胺素片的生物利用度评价[J]. 中国临床药理学与治疗学, 2013, 18(12): 1375-1382.

LUO Xi, CAI Ning-fang, GUO Xin, YU Peng, LIU Zhi, ZHENG Li-yun, CHENG Ze-neng. Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamine hydrochloride after oral administration[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(12): 1375-1382.

参考文献

[1] Patrini C, Griziotti A, Ricciardi L. Obese individuals as thiamin stores[J]. Int J Obes Relat Metab Disord, 2004,28(7): 920-924.
[2] Koski P, Bäckman C, Pelkonen O. Pharmacokinetics of thiamine in female Baltic salmon (Salmo salar L.) broodflsh [J]. Environ Toxicol Pharmacol, 2005,19(1): 139-152.
[3] Shimizu T, Hoshino H, Nishi S, et al. Anti-fatigue effect of dicethiamine hydrochloride is likely associated with excellent absorbability and high transformability in tissues as a vitamin B1 [J]. Eur J Pharmacol, 2010, 635(1/2/3):117-123.
[4] Pietrzak I, Baczyk K. Comparision of the thiamine level in blood and erythrocyte transketolase activity in hemodialyzed and nondialyzed patients during recombinant human erythropoietin therapy[J]. Miner Electrolyte Metab, 1997,23(3/4/5/6): 277-282.
[5] Lu J, Frank EL. Rapid HPLC measurement of thiamine and its phosphate esters in whole blood [J]. Clin Chem, 2008,54(5): 901-906.
[6] Zempleni J, Hagen M, Hadem U, et al. Utilization of intravenously infused thiamin hydrochloride in healthy adult males [J]. Nutrition Research, 1996,16(9): 1479-1485.
[7] Gerrits J, Eidhof H, Brunnekreeft JW, et al. Determination of thiamin and thiamin phosphates in whole blood by reversed-phase liquid chromatography with precolumn derivatization [J]. Methods Enzymol, 1997,279: 74-82.
[8] Losa R, Sierra MI, Fernández A, et al. Determination of thiamine and its phosphorylated forms in human plasma, erythrocytes and urine by HPLC and fluorescence detection: a preliminary study on cancer patients [J]. J Pharm Biomed Anal, 2005,37(5): 1025-1029.
[9] NoseY, Iwashima A. Intestinal absorption of thiamine propyl disulfide [J]. J Vitaminol (Kyoto), 1965, 11(3): 165-170.
[10] Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine [J]. Int J Clin Pharmacol Ther, 1996, 34(2): 47-50.
[11] Greb A, Bitsch R. Comparative bioavailability of various thiamine derivatives after oral administration [J]. Int J Clin Pharmacol Ther, 1998, 36(4): 216-221.

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