文章摘要
秦超,霍桂桃,王超,杨颖,姜华,苗玉发,杨艳伟,耿兴超,文海若.SD大鼠单次及重复28天给予尿素毒性研究[J].中国药事,2021,35(10):1132-1141
SD大鼠单次及重复28天给予尿素毒性研究
Toxicity Studies of Single-dose and 28 Days Repeated-dose of Urea in SD Rats
  
DOI：10.16153/j.1002-7777.2021.10.008
中文关键词: 尿素  SD大鼠  单次给药毒性  重复给药毒性
英文关键词: urea  SD rats  single-dose toxicity  repeated dose toxicity
基金项目:国家“重大新药创制”科技重大专项(编号 2018ZX09201017-001)
作者单位
秦超 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 
霍桂桃 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 
王超 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 
杨颖 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 
姜华 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 
苗玉发 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 
杨艳伟 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 
耿兴超 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 
文海若 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 
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中文摘要:
      目的：开展SD大鼠在单次及重复28天经口给予尿素的毒性研究，评价其毒性风险。方法：以尿素为受试物，分别采用单次和重复28天给予2种给药方案。单次给药毒性试验中，将20只SD大鼠分为对照组(给予去离子水)和给药组(给予尿素，10000 mg·kg-1)，受试物经口灌胃给予，之后连续观察临床症状并测定体重，给予尿素后第15天进行大体病理学检查。重复28天给药毒性试验将80只SD大鼠分为4个剂量组，即对照组(给予去离子水)、100 mg·kg-1组、300 mg·kg-1组和1000 mg·kg-1组，每组 20只。连续28天经口灌胃给予受试物，观察动物临床症状，定期测定体重及摄食量。末次给药前进行眼科学检查和尿生化检测；末次给药结束后进行血液学、血液凝固和血清生化学检测，采集脏器称重并进行组织病理学检查。结果：试验期间，所有给药组动物在给药后观察期内均未见异常临床症状。连续给予尿素28天后，给药组动物体重、摄食量与同期对照组比较均未见显著统计学差异(P＞0.05)，各项血液学检测、血液凝固和血清生化学检测，所有称重的组织脏器与同性别对照组动物比较均未见显著性差异(P＞0.05)，且眼科学检查未见异常，对照组和给药组所有动物的主要组织器官的病理学检查均未见异常。但给予尿素可导致动物尿液中尿蛋白含量升高(P＜0.01)、尿颜色加深(P＜0.01)和尿比重升高 (300 mg·kg-1组与对照组相比，P＜0.05；1000 mg·kg-1组与对照组相比，P＜0.01)，该现象与给药组动物体内大量尿素经肾脏代谢有关。结论：本研究单次经口给予尿素后未见动物死亡，认为其半数致死率的剂量在10000 mg·kg-1以上。大鼠对尿素的最大耐受剂量和未见毒性反应剂量均为1000 mg·kg-1。
英文摘要:
      Objective: To study the toxicity of single and repeated oral administration of urea in SD rats for 28 days, and to evaluate the risk of toxicity. Methods: Urea was used as the test substance. Two administration regimens were given for single time and for repeated 28 days, respectively. In the toxicity test of single administration, 20 SD rats were divided into control group (given deionized water) and administration group(given urea, 10000 mg·kg-1). The subjects were given orally and intragastrically administration. After that, the clinical symptoms were observed continuously and weight was measured. The toxicity test was repeated for 28 days, and 80 SD rats were divided into 4 dose groups, namely, control group (given deionized water), 100 mg·kg-1 group, 300 mg·kg-1 group and 1000 mg·kg-1 group, with 20 rats in each group. The subjects were given orally and intragastrically for 28 consecutive days. The clinical symptoms of the animals were observed. The body weight and food intake were measured regularly. Ophthalmology examination and urine biochemical test were performed before the last administration. After the end of the last administration, hematology, blood coagulation and serum biochemistry were detected. The organs were collected and weighed and histopathological examination was performed. Results: During the experiment, no abnormal clinical symptoms were found in all the animals in the administration group. Urea was administered continuously for 28 days, and there was no significant statistical difference in body weight and food intake between the treated group and the control group (P＞0.05). No significant difference of tissues weight, hematological tests, blood coagulation and serum biochemistry tests (P＞0.05) were found between the treated group and the control animals of the same sex. Ophthalmology examination was normal. Pathological examination of the main tissues and organs of all the animals in the control group and the administration group shows no abnormality. However, urea administration could increase the urine protein content (P＜0.01), deepen the urine color (P＜0.01) and increase the urine specific gravity (P＜0.05, compared with 300 mg·kg-1 group; P＜0.01, compared with 1000 mg·kg-1 group), which was related to the metabolism of a large amount of urea through the kidney in the treated group. Conclusion: In this study, no animals died after a single oral administration of urea, and the 50% fatality rate was thought to be above 10000 mg·kg-1. The maximum tolerated dose of urea and the dose of no toxic reaction were 1000 mg·kg-1.
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