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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 glipizide tablets in Chinese healthy volunteers. Methods: Twelve healthy subjects, half male and half female, were given a test preparation and were given a single pharmacokinetic study. After 14d washout period, they were given multiple administrations and were given an empty stomach once a day 1 consecutive tablets administered 7d. The concentrations of pioglitazone, glimepiride and their respective active metabolites in plasma samples from 12 subjects after single or multiple dosing were determined by LC-MS / MS. The pharmacokinetic parameters were calculated by DAS 3.0.4 , Using SPSS 13.0 statistical analysis of the main parameters. RESULTS: The main pharmacokinetic parameters of pioglitazone, ketopiglitazone, hydroxy pioglitazone, glimepiride and hydroxyglmetide in 12 subjects after single administration were as follows: 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) 261.0 ± 65.8 μg L-1, (60.8 ± 15.5) μg.L-1, AUC0-t (12 724.4 ± 3 268.4) μg.hL-1, (10 703.1 ± 3 057.8) μg.hL- (32 263.4 ± 7 961.8) μg.hL-1, (1 656.6 ± 890.1) μg.hL-1, and (706.6 ± 136.6) μg.hL-1 respectively. The steady-state AUCSS after multiple oral administrations were (11 939.9 ± 5 397.2) μg.hL-1, (9 551.0 ± 1 690.8) μg.hL-1, (32 159.8 ± 7 356.6) μg.hL-1, (1445.6 ± 1 047.7) μg.hL- 517.4 ± 124.5) μg.hL-1 respectively; Cav levels were (497.5 ± 224.9) μg.L-1, (340.3 ± 306.5) μg.L-1, (398.0 ± 70.4) μg.L- 43.65) μg.L-1, (21.56 ± 5.19) μg.L-1. After a single administration of ketopiglitazone and hydroxy pioglitazone t1 / 2 differences were statistically significant, the other was not statistically significant; after multiple administration, in addition to ketones pioglitazone (M-1), hydroxy pioglitazone M-2), the t1 / 2 and M-1 of glimepiride were statistically significant, while the other sex differences were not statistically significant. Conclusion: Both ketopiglitazone and hydroxy pioglitazone accumulate in vivo, whereas pioglitazone, glimepiride, and hydroxyglmeme have no accumulation. Pioglitazone, keto pioglitazone, glimepiride, and hydroxyglmeprol have achieved steady-state concentrations on day 5; the steady-state concentrations of hydroxy pioglitazone reach steady state on day 6 after multiple administrations.