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中国药物评价 ›› 2020, Vol. 37 ›› Issue (6): 422-427.

• 药物研究 • 上一篇    下一篇

通关散对大鼠长期毒性和毒代动力学研究

 李欣1,2, 冯群1,2, 赵涛2, 肖敏2, 荆凡波3, 周长凯3, 姚景春1,2*   

  1. 1. 鲁南制药集团股份有限公司, 中药制药共性技术国家重点实验室, 山东 临沂 273400;
    2. 鲁南制药集团股份有限公司新药安评中心, 山东 临沂 273400;
    3. 青岛大学附属医院, 山东 青岛 266100
  • 收稿日期:2020-06-29 修回日期:2020-07-23 出版日期:2020-12-28 发布日期:2020-12-28
  • 基金资助:
    山东省重大科技创新工程项目——基于《箧中秘宝方》中经方“通关散”的鼻用原位凝胶制剂研究(2018CXGC1304)

Study on Long-term Toxicity and Toxicokinetics of Tongguansan in Rats

  1. 1. Lunan Pharmaceutical Group Co. Ltd., State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine,Shandong Linyi 273400, China;
    2. Center for Drug Safety Evaluation of Lunan Pharmaceutical Group Corporation, Shandong Linyi 273400, China;
    3. Affiliated Hospital of Qingdao University, Shandong Qingdao 266100, China
  • Received:2020-06-29 Revised:2020-07-23 Online:2020-12-28 Published:2020-12-28

摘要: 目的:评价通关散对大鼠的长期毒性反应及毒代动力学,为临床安全用药提供参考。方法: 连续28 d给大鼠灌胃和鼻腔给予不同剂量的通关散,观察其给药期和恢复期大鼠一般状况、体重、摄食量变化,检测血常规、血生化指标,观察主要脏器并进行病理学检查,称取心、肝、脾、肾等脏器,计算脏脑系数。首次和末次给药后的不同时间点对各组大鼠静脉取血,用LC-MS/MS法测定血浆内苯甲酰乌头原碱、苯甲酰次乌头原碱和苯甲酰新乌头原碱的含量,DAS软件拟合毒代动力学参数。结果: 大鼠连续28 d给予0.125~1.25 g·kg-1通关散(相当于临床日用量的1.8~18倍),进行毒性的比较研究,发现鼻腔和灌胃给药大鼠状态正常,体重、摄食量正常,尿液学、血液学指标在正常范围内,各脏器外观正常,主要脏器的脏脑系数在正常范围内,眼科检查及组织病理检查未发现与药物相关的毒性反应。鼻腔给药1 h后血药浓度均低于定量下限0.5 ng·mL-1,灌胃给药时的药物体内暴露量与剂量呈正相关,但不同给药方式下,大鼠血浆内均未显示有药物蓄积现象。结论: 通关散鼻腔给药和灌胃给药28 d,均未产生明显的毒性反应和药物蓄积,可为临床安全剂量的确定提供参考。
  

关键词: font-size:medium, ">通关散;乌头碱;长期毒性;毒代动力学

Abstract: Objective: To evaluate long-term toxicity reaction and toxicokinetics of Tongguansan in rats, which provides scientific evidences for clinical application. Methods: Tongguansan was prepared to give rats by gavage and intranasal administration for 28 days continuously. General conditions during the terms of taking drugs and observations including amount of ingestion and body mass were observed. Blood routine, the biochemical indicators, and brain ratios were detected and pathological changes of important organs such as heart, liver, spleen, lung, kidney, brain and others were detected. LC-MS/MS method was used to determine the concentration of benzoylaconitine (BA), benzoylhypacoitine (BH) and benzoylmesaconine (BM) in rat plasma at different time points after single administration. Toxicokinetic data were analyzed by DAS software. Results: Rats were in normal conditions with administration of Tongguansan range from 0.125 to 1.25 g·kg-1, which was equal to 1.8 to 18 times of 70 kg adult′s daily expenses. Indexes of blood and urine were in normal range. There was no significant difference of brain ratios among the groups. No drug-related toxicity was known according to the histopathological examination. With the intranasal administration of Tongguansan, the concentrations of BA and BH were lower than 0.5 ng·mL-1 after one hour. The exposure in rats by gavage was positively related to the dosage of Tongguansan. However, there was no obvious accumulative toxicity with the different administrations. Conclusion: There was no obvious toxicity and accumulation in rats with the oral and intravenous administrations of Tongguansan for 28 consecutive days, which can provide reference for the determination of clinical safe dose.
  

Key words: font-size:medium, ">Tongguansan; Aconitine; Long-term toxicity; Toxicokinetics

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