中国药物警戒 ›› 2022, Vol. 19 ›› Issue (1): 57-61.
DOI: 10.19803/j.1672-8629.2022.01.12

• 基础与临床研究 • 上一篇    下一篇

佐匹克隆及其杂质对斑马鱼胚胎发育毒性的比较研究

尹婕, 南楠, 陈华*   

  1. 中国食品药品检定研究院,国家药品监督管理局化学药品质量研究与评价重点实验室,北京102629
  • 收稿日期:2020-10-10 出版日期:2022-01-15 发布日期:2022-01-20
  • 通讯作者: *陈华,男,主任药师,药品质量控制与检测分析。E-mail：chenhua@nifdc.org.cn
  • 作者简介:尹婕,女,博士,副研究员,药品质量控制与检测分析。
  • 基金资助:
    重大新药创制国家科技重大专项2017年度（2017ZX09101001）

Developmental toxicity of zopiclone and its impurities in zebrafish embryos

YIN Jie, NAN Nan, CHEN Hua*   

  1. National Institutes for Food and Drug Control, National Medical Products Administration Key Laboratory for Quality Research and Evaluation of Chemical Drugs, Beijing 102629, China
  • Received:2020-10-10 Online:2022-01-15 Published:2022-01-20

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摘要： 目的 对佐匹克隆及其主要杂质的斑马鱼胚胎发育毒性进行比较研究。方法 以斑马鱼胚胎为实验对象,在体视光学显微镜下观察佐匹克隆及其主要杂质（杂质A、B、C和2-氨基-5-氯吡啶）在不同暴露浓度时对斑马鱼胚胎发育情况的影响,包括胚胎致畸、致死情况的检测与统计。结果 佐匹克隆及其4个杂质对斑马鱼胚胎发育的毒性表型类似;毒性作用发生在胚胎器官的形成期;胚胎的畸形率和死亡率均呈一定的浓度依赖性升高;对胚胎发育的毒性由大到小的顺序为：杂质C、2-氨基-5-氯吡啶、杂质B、杂质A、佐匹克隆。结论 结合佐匹克隆的杂质谱、佐匹克隆上市药品中杂质的检出情况以及佐匹克隆与其4个主要杂质对胚胎发育毒性的比较结果,建议重点关注佐匹克隆的主要降解杂质2-氨基-5-氯吡啶,并将其作为特定杂质,在原料与制剂现行标准中增加对该杂质的控制,以保证本品的安全性和质量可控性。

关键词: 佐匹克隆, 杂质, 斑马鱼胚胎, 发育毒性, 毒性比较, 2-氨基-5-氯吡啶

Abstract: Objective To compare the toxicity of zopiclone and its main impurities on embryonic development of zebrafish. Methods Embryonic development of zebrafish was investigated under a stereo microscope at different concentrations of the drug. The teratogenicity and lethality of zebrafish embryos were statistically analyzed in conjunction with microscopic observation. Results Zopiclone and its impurities had a similar toxic phenotype to embryonic development of zebrafish and the toxic effects occurred during the development of embryonic organs. The results showed that both teratogenicity and the mortality rate of embryos were positively correlated with drug concentrations. The embryonic toxicity was the strongest in impurity C, followed by 2-amino-5-chloropyridine, impurity B, impurity A, and zopiclone. Conclusion Based on the impurity spectrum of zopiclone, the contents of impurities in marketed drugs and the experimental toxicity results of zopiclone and its major impurities on embryonic development, it was recommended that 2-amino-5-chloropyridine be controlled as a specified impurity with a strict limit in the quality specifications of zopiclone materials and preparations in order to ensure the safety and quality of this drug.

Key words: zopiclone, impurities, zebrafish embryo, developmental toxicity, toxicity comparison, 2-amino-5-chloropyridin

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