苯磷硫胺片在健康人体内的药动学研究

Pharmacokinetics Study of Benfotiamine Tablet in Healthy Volunteers

目的:研究苯磷硫胺片在中国健康志愿者中单次及连续多次口服给药的药动学特征。方法:12名健康志愿者采用随机、开放试验设计,单次及连续多次给予苯磷硫胺片300 mg后,采用高效液相色谱-荧光(HPLC-FLU)法测定血浆及红细胞中硫胺素及二磷酸硫胺素(TDP)的浓度。使用WinNonlin 6.1软件对单次及多次给予苯磷硫胺片后血浆中硫胺素的浓度进行房室模型拟合并计算主要药动学参数,以梯形面积法计算红细胞中TDP的药-时曲线下面积(AUC0-24 h)。结果:单次及多次给药后血浆中硫胺素药动学参数分别为:t1/2z(1.6±0.4)、(2.1±0.4)h,AUC0-24 h(1 819.9±336.3)、(3 034.8±806.9)μg·h/L,AUC0-∞(1 835.3±331.7)、(3 085.8±774.0)μg·h/L,cmax(520.5±130.2)、(679.4±136.6)μg/L,CL/F(177.1±30.5)、(116.7±33.6)L/h,Vd/F(401.3±129.2)、(334.2±81.3)L,MRT(4.3±0.9)、(5.3±0.4)h。单次及多次给药后红细胞中TDP的AUC0-24 h分别为(3 432.9±815.5)、(5 013.4±965.7)μg·h/L。结论:连续多次给药后,血浆硫胺素的浓度有所累加,消除减慢;红细胞中TDP存在蓄积现象,达到稳态浓度后,24 h内波动很小。

OBJECTIVE： To investigate the pharmacokinetics of single or multiple oral doses of Benfotiamine tablet in healthy Chinese volunteers. METHODS： The open, random clinical trial involved 12 healthy volunteers who received a single or multiple doses of benfotiamine 300 mg to study the pharmacokinetic characteristics of benfotiamine. The concentrations of thia- mine and thiamine diphosphat （TDP） in plasma or erythrocyte were determined by HPLC-FLU. The main pharmacokinetic param- eters were calculated by compartmental model fitting using WinNonlin 6,1 program, AUC0-24 h of TDP in erythrocyte was calculat- ed by trapezoidal method. RESULTS： The main pharmacokinetic parameters of thiamine in plasma after single and multiple dos- es were as follows： t1/2 were （1.6 ± 0.4）h and （2.1 ± 0.4）h, AUC0-2,h were （1 819.9 ± 336.3）μg.h/L and （3 034.8 ± 806.9）lxg.h/L, AUCo-∞ were （1 835.3 ± 331.7） μg,h/L and （3 085.8 ± 774.0）μg-h/L, Cmax were （520.5 ± 130.2）/ag/L and （679.4 ± 136.6）μg/L, CL/F were （177.1±30.5） L/h and （116.7±33.6） L/h; VjF were （401.3± 129.2）L and （334.2 ±81.3）L; MRT were （4.3± 0.9）h and （5.3 ± 0.4） h, respectively. AUC0-24 h of TDP in erythrocyte after single and multiple doses were （3 432.9 ± 815.5）μg. lgL and （5 013.4 ± 965.7）μg. h/L, respectively. CONCLUSIONS： After multiple doses, the thiamine in plasma appears to be accumulated and its elimination is decreased. TDP in erythrocyte also shows accumulation, and its level remains stable within 24 h when the sieady state achieves.