中国药物警戒 ›› 2025, Vol. 22 ›› Issue (10): 1114-1119.
DOI: 10.19803/j.1672-8629.20250436

• 基础与临床研究 • 上一篇    下一篇

N-亚硝基布美他尼体外致突变性风险评价

蒋晨晨1,2, 靳龙龙3△, 寇小旋1,2, 宋捷1,2, 石皓琨4, 黄勤4#, 文海若1,2,*   

  1. 1中国食品药品检定研究院安全评价研究所,北京 100176;
    2药品监管科学全国重点实验室,北京 102629;
    3中国食品药品检定研究院标准物质和标准化管理中心,北京 102629;
    4桂林南药股份有限公司,广西 桂林 541004
  • 收稿日期:2025-07-04 出版日期:2025-10-15 发布日期:2025-10-20
  • 通讯作者: *文海若,女,博士,研究员,药理毒理学。E-mail: wenhairuo@nifdc.org.cn;#为共同通信作者。
  • 作者简介:蒋晨晨,女,硕士,遗传毒理学。△为并列第一作者。
  • 基金资助:
    国家自然科学基金资助项目（82473889）; 药品监管科学全国重点实验室课题“药品杂质遗传毒性评价新技术和生物标志物研究（2023SKLDRS0128）”

In vitro Evaluation of Mutagenicity Risk by N-nitroso Bumetanide

JIANG Chenchen1,2, JIN Longlong3△, KOU Xiaoxuan1,2, SONG Jie1,2, SHI Haokun4, HUANG Qin4#, WEN Hairuo1,2,*   

  1. 1Institute of Safety Evaluation, National Institutes for Food and Drug Control, Beijing 100176, China;
    2State Key Laboratory of Drug Regulatory Science, Beijing 102629, China;
    3National Institutes for Food and Drug Control, Center of Reference Standards and Standardization, Beijing 102629, China;
    4Guilin Pharmaceutical Co., Ltd., Guilin Guangxi 541004, China
  • Received:2025-07-04 Online:2025-10-15 Published:2025-10-20

PDF (PC)

60

摘要： 目的 评估 N-亚硝基布美他尼的体外致突变性风险,为其安全性评价提供依据。方法 采用 Derek Nexus 和 Sarah Nexus 软件进行构效分析,预测其致突变性及警示结构;参照欧洲药品管理局（European Medicines Agency, EMA）指南,开展增强细菌回复突变试验（使用鼠伤寒沙门氏菌TA98、TA100、TA1535、TA1537和大肠杆菌WP2 uvrA（pKM101）菌株,在无代谢活化、30%大鼠S9和 30%仓鼠 S9 代谢活化及预培养30 min条件下进行）;同时进行小鼠淋巴瘤细胞tk基因突变试验（Mouse Lymphoma Assay,MLA）,检测其在不同处理条件下的细胞毒性和突变频率。结果 构效预测显示,Derek Nexus因N-亚硝基结构预测其存在细菌突变风险（评级“貌似可信”）,Sarah Nexus评级为“模棱两可”。增强细菌回复突变试验中,每皿125~5 000μg剂量下,各菌株回复突变菌落数未明显增加;MLA试验中,312.5~2 500μg·mL-1浓度范围内,细胞相对总生长率（Relative Total Growth,RTG）未见明显毒性,突变频率与阴性对照组相比无明显差异,结果均为阴性。结论 N-亚硝基布美他尼在体外试验条件下未显示致突变性风险,为其风险评估提供参考。

关键词: N-亚硝基布美他尼, 致突变性, 细菌回复突变试验, 小鼠淋巴瘤细胞试验, 构效分析, 药物安全性评价

Abstract: Objective To evaluate the mutagenicity risk of N-nitroso bumetanide in vitro and provide data for its safety assessment. Methods Structure-activity relationships were analyzed using Derek Nexus and Sarah Nexus software to predict mutagenicity and structural alerts. An enhanced bacterial reverse mutation test was conducted according to EMA guidelines using Salmonella typhimurium TA98, TA100, TA1535, TA1537, and Escherichia coli WP2 uvrA(pKM101) strains in the absence of post-mitochondrial fraction (S9), and also in the presence of 30% rat liver s9, as well as 30% hamster liverS9,followed by 30 min of pre-incubation. Additionally, a mouse lymphoma assay (MLA) was performed to detect cytotoxicity and mutation frequency under different treatment. Results In terms of structure-activity, Derek Nexus predicted the bacterial mutagenicity risk (rated as “plausible”) due to the N-nitroso structure while Sarah Nexus rated it as “ambiguous”. In the enhanced bacterial reverse mutation test, no obvious increase in revertant colonies of any strain was observed at doses of 125-5 000 μg per plate. In the MLA, the relative total growth (RTG) pointed to no obvious toxicity at concentrations of 312.5-2 500 μg·mL-1, and the mutation frequencies did not differ significantly from those of the negative control, with all the results being negative. Conclusion N-nitroso bumetanide does not pose any mutagenicity risk when tested in vitro.

Key words: N-nitroso Bumetanide, Mutagenicity, Bacterial Reverse Mutation Test, Mouse Lymphoma Assay, Structure-Activity Analysis, Drug Safety Evaluation

中图分类号: