Beagle犬灌胃给药磷酸瑞格列汀的重复毒性研究  

Toxicity of retagliptin phosphate in beagle dogs following repeated gavage administration

作　　者：周晓冰[1] 张琳[1] 张连山[2] 孙立[1] 苗玉发[1] 李珊珊[1] 刘芳[1] 杨艳伟[1] 汪巨峰[1] 李波[1] 

机构地区：[1]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,北京100176 [2]江苏恒瑞医药股份有限公司,连云港222047

出　　处：《中国新药杂志》2016年第5期503-507,共5页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项(2012ZX09302001)

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。Objective： To evaluate the preclinical toxicity of retagliptin phosphate（ SP2086） in beagle dogs following repeated gavage administration. Methods： Beagle dogs were randomly divided into four groups： vehicle control,retagliptin phosphate 5,10 and 50 mg·kg^- 1group. Each group included eight animals with female and male in half. All animals were intravenously given vehicle or test drug every day for consecutive 37 days with14-day recovery. Then a series of toxicological parameters were determined and drug toxicokinetics was analyzed.Results： Following repeated gavage administration of different doses of test drug,there were no obvious abnormalities related to the test drugofbody weight,food consumption,body temperature,electrocardiogram,blood pressure,urinalysis,serum chemistry and hematology. No histopathological findings were found in all test drug-treated groups. The toxicokinetic study showed a dose-dependent increase of Cmaxand AUC0- tof retagliptin phosphate and its esterolytic metabolites,suggesting no obvious accumulation of retagliptin phosphate in beagle dogs after repeated dosing. Conclusion： There is no obvious toxic reactions for retagliptin phosphate after repeated dosing in beagledogs at 50 mg·kg^- 1,which lays foundation for the drug to enter into human clinical trial.

关 键 词：磷酸瑞格列汀 BEAGLE犬 安全性 

分 类 号：R99[医药卫生—毒理学]