国产甘精胰岛素注射剂在Beagle犬体内的毒代动力学研究

Toxicokinetic study of insulin glargine injection in Beagle dogs

目的:探究国内生产的甘精胰岛素注射剂与国外上市甘精胰岛素注射剂(来得时)在Beagle犬体内的毒代动力学过程。方法:40只健康Beagle犬随机分为4组,皮下注射给药分别为国产甘精胰岛素低剂量组A(0.5 U/kg)、中剂量组B(1.0 U/kg)以及高剂量组C(1.5 U/kg)、来得时作为对照组D(1.5 U/kg),连续皮下注射给药30 d,于第1天、第15天、第30天不同时间点经静脉采集血样,RIA法检测血浆中胰岛素的浓度;用DAS 2.2拟合计算毒代动力学参数,SPSS17.0进行统计学检验,并分析是否会在体内蓄积。结果:A组皮下注射给药后第1天和第30天的平均AUC0-t分别为(870.24±194.30)、(723.01±223.88)μU·m L-1·h,平均Cmax分别为(98.55±41.24)、(84.92±25.64)μU/m L;B组皮下注射给药后第1天和第30天的平均AUC0-t分别为(1 298.92±386.13)、(1 375.53±376.68)μU·m L-1·h,平均Cmax分别为(157.58±46.89)、(212.90±72.71)μU/m L;C、D组皮下注射给药后第1天平均AUC0-t分别为(1 777.91±209.46)、(1 960.81±171.56)μU·m L-1·h,平均Cmax分别为(231.49±36.37)、(232.87±32.09)μU/m L;第30天的平均AUC0-t分别为(1 734.59±612.29)、(1 639.90±285.91)μU·m L-1·h,平均Cmax分别为(289.30±121.87)、(247.64±44.29)μU/m L。结论:国产甘精胰岛素注射液和对照制剂(来得时)在Beagle犬体内多次给药后没有蓄积现象,这与Beagle犬体内并未有出现毒性反应的结果相一致。

AIM： To investigate the toxicokinetic behaviors of domestic and imported insulin glargine injection in Beagle dogs. METHODS： Forty healthy Beagle dogs were randomly divided in- to four groups. The levels of insulin were subcutane- ously given at domestic insulin glargine Low group A （0.5 U/kg）, Middle group B （1.0 U/kg）, High group C （ 1.5 U/kg） and group D Lantus（ 1.5 U/ kg）, respectively for 30 days. Blood samples were collected at preset time points on day 1, day 15 and day 30; RIA method was used for determination of insulin levels in plasma concentration; calculation of toxicokinetic parameters was completed by using DAS 2.2 software; SPSS 17.0 was used for statistical analysis. RESULTS： The average AUC0-t of group A was （ 870.24±194.30 ） and （ 723.01±223.88） μU·m L^-1·h on day 1 and day 30 after subcutaneous administration; the mean Cmax was （98.55 ±1.24）, （84.92 ±25.64）μU·m L^-1. Average AUC0-t of group B was （ 1 298.92 ± 386.13 ） and （1 375.53 ± 376.68 ） μU·m L^-1·h on day 1 and day 30; the mean Cmax was （157.58 ±46.89）, （212.90 ± 72.71 ） μU·m L^-1, individually, And the average AUC0-t of the group C and group D on first day was （1 777.91 ± 209.46）, （i 960.81 ± 171.56） μU·m L^-1 ± h; the mean Cmax was （231.49 ±36.37） and （232.87 ±32.09） μU/ mL; the average AUC0-t of 30th day individually was （1 734.59±612.29）, （1 639.90 ±285.91）μU·m L^-1·h; the average Cmax was （289.30 ± 121.87）, （247.64 ±44.29） μU/mL. CONCLUSION： Domestic insulin glargine injection and reference agent （Lantus. Sanofi） in beagle dogs have no accumulation phenomenon after multiple adminis- trations, which was consistent with the results in Beagle dogs.