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

作　　者：张星艳[1,2] 李亚卓[2] 魏滋鸿 武卫党[2] 李薇[2] 路江杰 朱虹 张宗鹏[2] 曾勇[2] 李俊[1] ZHANG Xingyan;LI Yazhuo;WEI Zihong;WU Weidang;LI Wei;LU Jiangjie;ZHU Hong;ZHANG Zongpeng;ZENG Yong;LI Jun(College of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, China;State Key Laboratory of Drug Delivery Technology and Pharmaeokinetics, Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co. Ltd, Tianjin 300193, China;Tianmai Biological Technology Development Company Limited, Hefei 230601, Anhui, China)

机构地区：[1]安徽医科大学药学院 [2]天津药物研究院新药评价有限公司释药技术与药代动力学国家重点实验室,天津300193 [3]合肥天麦生物科技发展有限公司

出　　处：《中国临床药理学与治疗学》2017年第9期992-997,共6页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家"重大新药创制"科技重大专项(2012ZX09304002);国家重点研发计划(2016YFE0121400)

摘　　要：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.

关 键 词：甘精胰岛素 毒代动力学 BEAGLE犬 皮下注射 

分 类 号：R965.2[医药卫生—药理学]