Beagle犬灌胃给药磷酸瑞格列汀的重复毒性研究

发布时间：2018-03-22 08:28

本文选题：磷酸瑞格列汀　切入点：Beagle犬　出处：《中国新药杂志》2016年05期 　论文类型：期刊论文

【摘要】：目的:通过对Beagle犬重复灌胃(ig)给药磷酸瑞格列汀(研发代码:SP2086),评价其多次给药的毒性反应。方法:按体重随机将Beagle犬分成4组,分别为溶媒对照组、低(5 mg·kg-1)、中(10 mg·kg-1)和高(50 mg·kg-1)剂量组,每组8只动物,雌雄各半。经ig给药,qd,连续给药37 d,恢复期为14 d。然后进行各项毒理学指标检测和药物毒代动力学分析。结果:Beagle犬37 d重复ig给药不同剂量的供试品,动物的临床症状、体重、进食量、体温、心电图、血压、尿液分析、血清生化和血液学检测等各项指标未见与供试品相关的改变。组织病理学分析显示动物在多次供试品给药后未见异常改变。毒代动力学分析结果显示在连续给药37 d后,Beagle犬体内SP2086及其酯水解代谢物SP2086酸的Cmax和AUC0~t增加值与剂量增加基本成正比,SP2086在动物体内无明显蓄积。结论:Beagle犬ig给药供试品磷酸瑞格列汀的未观察到有害作用剂量(NOAEL)为50 mg·kg-1,此结果为药物进入临床试验奠定了基础。
[Abstract]:Objective: to evaluate the toxicity of repeated administration of rieglentin phosphate (R & D code: SP2086) in Beagle dogs. Methods: Beagle dogs were randomly divided into 4 groups according to their body weight. The rats in the low dose group of 5 mg kg-1 (10 mg kg-1) and the high dose of 50 mg kg-1) were treated with 8 animals in each group. Half of both sexes were given QD ig for 37 days and the recovery period was 14 days. The toxicological indexes and pharmacokinetic analysis were carried out. Results the clinical symptoms and body weight of different doses of different doses of the drug were repeatedly given to Beagle Dog by ig for 37 days. Food intake, body temperature, electrocardiogram, blood pressure, urine analysis, No changes were found in serum biochemical and hematological tests. Histopathological analysis showed that no abnormal changes were found in animals after multiple doses of the drug. The results of pharmacokinetics showed that the drug was given continuously. After 37 days, the increase of Cmax and AUC0~t of SP2086 and its ester hydrolytic metabolite SP2086 acid in Beagle dogs was in direct proportion to the increase of the dose. Conclusion there is no significant accumulation of repaglentin phosphate in the body of Beagle dogs. Conclusion the harmful effects of repaglentin phosphate on 30% Beagle dogs were not observed. The action dose of NOAELwas 50 mg kg -1, which laid a foundation for clinical trial.
【作者单位】：中国食品药品检定研究院国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室;江苏恒瑞医药股份有限公司;
【基金】：国家“重大新药创制”科技重大专项(2012ZX09302001)
【分类号】：R965

【共引文献】