重组人胰高血糖素类多肽1(7-36)在2型糖尿病患者中的药动学研究

Pharmacokinetics Study of rhGLP1(7-36) in Type 2 Diabetes Patients

目的:研究重组胰高血糖素类多肽1(7-36)[rhGLP-1(7-36)]在2型糖尿病患者单次和多次给药的药动学特征。方法:将轻型2型糖尿病患者16例,随机分为0.1、0.2mg剂量组,每组8例,试验前1天给予同体积生理盐水,第1～5天每日3餐前5min腹部皮下注射rhGLP-1(7-36)。采用酶联免疫吸附试验(ELISA)法分别测定给药前1天及给药第1、5天各时间点(给药前0min及给药后5、10、20、30、40、50、60、70、90、120min)rhGLP-1(7-36)的血药浓度以及第2～4天谷峰浓度。应用DAS2.1.1软件计算药动学参数,SPSS13.0软件进行统计分析。结果:两组首次给药药动学参数分别为:tmax(22.5±11.65)、(17.50±7.07)min,t1/2z(15.78±6.82)、(12.12±5.52)min,cmax(142.69±96.64)、(407.29±287.48)ng/L,AUC0-120min(3783.64±2177.03)、(9034.88±4262.92)ng.min/L,MRT0-120min(30.69±6.32)、(26.44±6.02)min;2组末次给药药动学参数分别为:tmax(26.25±7.44)、(16.25±5.18)min,t1/2z(20.72±13.44)、(12.97±6.46)min,cmax(118.05±38.39)、(361.11±217.81)ng/L,AUC0-120min(3321.91±993.47)、(9514.97±5077.89)ng.min/L,MRT0-120min(30.34±4.81)、(24.29±4.52)min;多次给药的蓄积指数分别为(0.96±0.32)、(0.88±0.43)。两组间首次给药的药动学参数AUC0-120min、AUC0-∞、cmax比较差异有统计学意义,在0.1～0.2mg剂量范围内呈剂量依赖性;两组间末次给药各药动学参数比较,差异均无统计学意义;两组内首末次给药的药动学参数比较差异均无统计学意义。结论:2型糖尿病患者腹部皮下单剂量注射rhGLP-1(7-36)后,在0.1～0.2mg剂量范围内符合线性药动学过程;多次给药不会引起药动学参数的改变,体内无蓄积。

OBJECTIVE： To investigate the pharmacokinetic characteristics of rhGLP-1 （7-36） in type 2 diabetes patients with single-dose and multiple-dose administration. METHODS： 16 type 2 diabetes patients were randomly divided into 0.1 mg group and 0.2 mg group （n=8）. They were given same volume of normal saline a day before trial and subcutaneous injection of rhGLP-I （7-36） 5 min before meal on first to fifth day; ELISA method was used to determine the blood concentration of rhGLP-1 （7-36） a day before trial and on the first and fifth day as well as the trough and peak concentration on the second to forth day. Pharmacoki- netic parameters were calculated by DAS 2.1.1 software; statistical analysis was conducted by SPSS13.0 software. RESULTS： The pharmacokinetic parameters of 2 groups after first administration were as follows： tmax（22.5 ± 11.65） min vs.（17.50 ± 7.07）min; t1/2 （15.78 ± 6.82）min vs. （12.12 ± 5.52）min; Cmax （142.69 ± 96.64） ng/L vs. （407.29 ± 287.48） ng/L; AUC0-120 min（3 783.64 ± 2 177.03） ng-min/L vs.（9 034.88 ± 4 262.92）ng.min/L; MRT0-120 min（30.69 ± 6.32）min vs.（26.44 ± 6.02）min. The pharmacokinetic parameters of 2 groups after last administration were as follows：tmax（26.25 ± 7.44）min vs.（16.25 ± 5.18）min; t1/2（20.72 ±_ 13.44）min vs.（12.97 ± 6.46）min; Cmax（118.05 ± 38.39）ng/L vs.（361.11 ± 217.81）ng/L; AUC0-120 min（3 321.91 ± 993.47）ng.min/L vs.（9 514.97 ± 5 077.89） ng.min/L;MRT0-120min（30.34 ± 4.81）min vs.（24.29 ± 4.52）min. The accumulation index of 2 groups were （0.96 ± 0.32） and （0.88 ± 0.43） with multiple dose. The pharmacokinetic parameters AUCo-0-120min, AUC0-120 min and 0-∞ of 2 groups had significant difference after first dose, in dose-dependent manner in the dose range of 0.1-0.2 mg; the pharmacokinetic parameters of 2 groups have no signifi- cant difference after last administration; there was no significant difference in pharmacokinetic parameters between first and last ad- ministration in 2 groups. CONCLUSIONS： After giving single dose of rhGLP-1 （7-36） subcutaneously, the pharmacokinetics nearly fits linear dynamic feature in the range of 0.1-0.2 mg; pharmacokinetic parameters will not change, and with no accumulation after multiple-dose injection.