复方盐酸吡格列酮格列美脲片在健康人体的药动学

Pharmacokinetics of compound pioglitazone hydrochloride and glimepiride tablet in healthy Chinese volunteers

目的:研究复方盐酸吡格列酮格列美脲片在中国健康人体内的单次、多次给药药动学。方法:12名健康受试者,男女各半,给予受试制剂1片,进行单次给药药动学研究;经过14d清洗期进入多次给药试验,每天清晨空腹给药1次,每次1片连续给药7d。采用LC-MS/MS法测定12名受试者单次、多次给药后血浆样品中吡格列酮、格列美脲及其各自的活性代谢产物的浓度,DAS 3.0.4计算其药动学参数,采用SPSS 13.0对主要参数进行统计分析。结果:12名受试者单次给药后吡格列酮、酮基吡格列酮、羟基吡格列酮、格列美脲、羟基格列美脲的主要药动学参数如下:t1/2(12.2±5.8)h,(36.2±12.1)h、(36.7±12.5)h、(5.6±3.8)h、(9.5±5.5)h;tmax:(2.1±0.8)h、(22.8±9.7)h、(22.5±10.2)h、(3.2±0.8)h、(4.6±1.4)h;Cmax:(921.0±251.1)μg.L-1、(174.9±58.2)μg.L-1、(508.8±155.5)μg.L-1、(261.0±65.8)μg.L-1、(60.8±15.5)μg.L-1;AUC0-t(12 724.4±3 268.4)μg.h.L-1、(10 703.1±3 057.8)μg.h.L-1、(32 263.4±7 961.8)μg.h.L-1、(1 656.6±890.1)μg.h.L-1、(706.6±136.6)μg.h.L-1;多次口服给药后稳态AUCSS分别为(11 939.9±5 397.2)μg.h.L-1、(9 551.0±1 690.8)μg.h.L-1、(32 159.8±7 356.6)μg.h.L-1、(1 445.6±1 047.7)μg.h.L-1、(517.4±124.5)μg.h.L-1;Cav分别为(497.5±224.9)μg.L-1、(1 340.0±306.5)μg.L-1、(398.0±70.4)μg.L-1、(60.24±43.65)μg.L-1、(21.56±5.19)μg.L-1。单次给药后酮基吡格列酮及羟基吡格列酮的的t1/2差异均具有统计学意义,其他的均无统计学意义;多次给药后,除酮基吡格列酮(M-1)、羟基吡格列酮(M-2)、格列美脲的t1/2及M-1的tmax性别差异具有统计学意义,其余的性别差异无统计学意义。结论:酮基吡格列酮及羟基吡格列酮在体内均有蓄积作用,而吡格列酮、格列美脲、羟基格列美脲则无蓄积作用。吡格列酮、酮基吡格列酮、格列美脲、羟基格列美脲在第5天已达到稳态浓度;羟基吡格列酮经多次给药后在第6天达到稳态浓度。

OBJECTIVE To study the pharmacokinetics of compound pioglitazone hydrochloride and glimepiride tablet（30 mg/2 mg/tablet） with single or multiple dose oral administration in Chinese healthy volunteers.METHODS In single-dose group,12 volunteers（6 male and 6 female） received one compound pioglitazone hydrochloride and glimepiride tablet;in multiple-dose group after 14 days washout period,orally given with one tablet in the morning for 7 days.The concentrations of pioglitazone and glimepiride and their active metabolites were determined using the established HPLC-MS/MS methods.DAS 3.0.4 software was used to calculate pharmacokinetic parameters and SPSS 13.0 software was used to evaluate the parameter differences.RESULTS The main pharmacokinetic parameters of pioglitazone、M-1（keto derivative of pioglitazone）、M-2（hydroxy derivatives of pioglitazone）、glimepiride、G1（cyclohexyl hydroxy methyl derivative of glimepiride） after single-dose and multiple-dose administration,respectively,were as follows：T1/2（12.15±5.85）h,（36.21±12.07）h、（36.68±12.51）h、（5.59±3.79）h、（9.46±5.52）h;Tmax ：（2.08±0.85）h、（22.83±9.74）h、（22.50±10.17）h、（3.25±0.75）h、（4.58±1.38）h;Cmax：（921.05±251.06）μg·L-1、（174.89±58.15）μg·L-1、（508.82±155.52）μg·L-1、（260.98±65.76）μg·L-1、（60.78±15.53）μg·L-1;AUC0-t（12724.38±3268.39）μg·h·L-1、（10703.08±3057.78）μg·h·L-1、（32263.38±7961.84）μg·h·L-1、（1656.59±890.14）μg·h·L-1、（706.63±136.56）μg·h·L-1;AUCSS：（11939.86±5397.16）μg·h·L-1、（9551.02±1690.84）μg·h·L-1、（32159.82±7356.64）μg·h·L-1、（1445.64±1047.71）μg·h·L-1、（517.45±124.50）μg·h·L-1;Cav（497.49±224.88）μg·L-1、（1339.99±306.53）μg·L-1、（397.96±70.45）μg·L-1、（60.24±43.65）μg·L-1、（21.56±5.19）μg·L-1.In single dose group,all these parameters had no sex defference other than t1/2 of M-1and M-2.After multiple dosing,the main parameters of the five compounds had no sex difference,except t1/2 of M-1,M-2,glimepiride,and Tmax of M-1.CONCLUSION No accumulation was observed except for M-1 and M-2.M-2 reach the steady-state concentration at the sixth day,while others were at the fifth day.