米格列奈钙片单、多次给药人体药代动力学研究

Pharmacokinetics of mitiglinide calcium tablets in human healthy volunteers

目的研究米格列奈钙片在健康人体单、多次给药的药代动力学。方法40名健康志愿者，随机平均分为4组（男女各半），单次给药分别口服米格列奈钙片5、10、20mg，多次给药10mg，q8h×7d。按试验方案采血，高效液相色谱-质谱联用法测定血浆中米格列奈浓度，DAS2．0软件计算药代动力学参数。结果健康受试者单次给药5、10、20mg主要药代动力学参数分别为：tmax（0．27±0．10）、（0．39±0．39）和（0．34±0．16）h；Cmax（697．114-168．83）、（1293．56±293．59）和（1716．43±276．29）μg·h-1·L-1；t1／28（2．44±2．32）、（1．32±0．45）和（2．38±2．22）h；AUC0-1（797．8±149．0）、（1545．1±240．5）和（2474．7±624．6）μg·h-·L-。多剂量给药10mg达稳态后，主要药代动力学参数为tmax（0．27±0．07）；Cmax（1149．99±297．61）μg·h-1·L-1；t1／2β（1．40±0．33）h；AUC0-1（1236．84-327．6）μg·h-1·L-1；Cmin（5．68±2．32）μg·h-1·L-1；AUCss（1236．78±327．64）μg·h-1·L-1；Cav（154．60±40．96）μg·h-1·L-1；Dr（7．45±0．68）；蓄积因子R（O．93±0．30）。结论米格列奈钙片口服给药5—20mg剂量范围内，体内过程呈线性；10mg，q8h连续多次7d，血药浓度d4已达稳态，体内无蓄积；且男女性别间体内过程也未见显著性差别。

Aim To investigate the pharmacokinetics of mitiglinide calcium tablets with a single and multi - dose p. o. administration in Chinese healthy volunteers. Methods 40 healthy volunteers were randomly divided into four groups with 5 male and 5 females in each group. The volunteers in three groups were administrated with single dose of mitiglinide calcium tablets 5,10,20 mg. respectively. The last group was administrated with the dose of mitiglinide calcuim tablets 10 mg, tid, till the seventh day. Blood samples were collected accord- ing to the protocol and plasma concentration of mitiglinide were measured by validated LC - MS/MS. DAS2.0 software was performed for calculating pharmacokinetic parameters. Results The main phamlacokinetics parameters of mitiglinide in volunteers who were adminis- trated with a single dose of 5,10,20 mg were as follows ：tmax （0.27 ± 0. 10）, （0.39 ± 0.39）and（0.34 ± 0.16）h; Cmax （697.11 ± 168. 83）,（1293.56 ±293.59）and（1716.43 ±276.29）μg·h-1·L-1;tl/2a（2.44 ±2.32）,（1.32 ±0.45）and（2.38 ±2.22）h;AUC0-1 （797.8 ± 149.0）, （ 1545.1 ± 240.5 ） and （ 2474.7 ± 624.6 ）μg·h-1·L-1, respectively. The main pharmacokinetics parameters of mitiglinide after multi - dose （ 10 mg ） administration were as follows ：tin= （0. 27 ± 0. 07 ）, Cmax （ 1149.99 ± 297.61 ） μg·h-1·L-1, t 1/2β （1.40 ±0.33）h,AUC0-1（1236.8 ±327.6）μg·h-1·L-1 ,Cmax（5.68 ±2.32） μg·h-1·L-1 ,AUCss（1236.78 ±327.64） μg·h-1·L-1,Cav（154.60 ±40.96）μg·h-1·L-1,DF（7.45 ±0.68）,R（0.93 ±0.30）. Conclusion After administration of mult-dose mitiglinide calium tablets（ 10 mg tid p. o. ） ,plasma concentrations of mitiglinide have been in steady state till fourth day and have no ob- vious accumulation in vivo. Increase of mitiglinide calcium tablets dosage（5 -20 rag）is positively calculated with increase of Cmax and AUC0-1 and simultaneously with no significant difference of physiological disposition between the male and female.