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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 toxicity of repeated administrations of repaglinide (code: SP2086) to Beagle dogs by repeated intragastric (ig) administration. Methods: Beagle dogs were randomly divided into 4 groups according to body weight: vehicle control group, low (5 mg · kg -1), medium (10 mg · kg -1) and high (50 mg · kg -1) Eight animals in each group, half male and half female. Ig administration, qd, continuous administration of 37 d, recovery period of 14 d. Then carry out various toxicological indicators detection and drug toxicokinetic analysis. Results: Beagle dogs were administered ig with different dosage of ig on 37 days. The clinical symptoms, body weight, food intake, body temperature, electrocardiogram, blood pressure, urinalysis, serum biochemistry and hematological examination of animals were not observed Test-related changes. Histopathological analysis showed no abnormal changes in animals after multiple administrations of the test product. The results of toxicokinetic analysis showed that the Cmax and AUCo-t increase of SP2086 and its ester hydrolase SP2086 in Beagle dogs were basically proportional to the dose increase after 37 days of continuous administration, while no significant accumulation of SP2086 in animals was observed. CONCLUSION: The NOAEL of igrigine phosphate administered to Beagle dogs was 50 mg · kg-1, which laid the foundation for the drug to enter clinical trials.