中国药物警戒 ›› 2022, Vol. 19 ›› Issue (7): 712-716.
DOI: 10.19803/j.1672-8629.2022.07.04

• 机制性模型在药物研发和评价中的应用专栏（一） • 上一篇    下一篇

基于计算模型结合数据库技术快速评价注射用左奥硝唑及其主要杂质的潜在神经毒性

张斗胜, 王晨#, 许明哲*   

  1. 中国食品药品检定研究院,北京 102629
  • 收稿日期:2022-02-15 出版日期:2022-07-15 发布日期:2022-07-12
  • 通讯作者: *许明哲,男,博士,主任药师,抗感染药物质量评价研究。E-mail：xumzhe@nifdc.org.cn。#为共同通信作者。
  • 作者简介:张斗胜,男,博士,主任药师,抗感染药物质量评价研究。
  • 基金资助:
    重大新药创制国家科技重大专项2015年度（2015ZX09303001）; 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课题（10300590126）

Rapid evaluation of potential neurotoxicity of levornidazole for injection and its main impurities based on computational models and database technology

ZHANG Dousheng, WANG Chen#, XU Mingzhe*   

  1. Institute for Drug Control, National Institutes for Food and Drug Control, Beijing 102629, China
  • Received:2022-02-15 Online:2022-07-15 Published:2022-07-12

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摘要： 目的 快速评价注射用左奥硝唑及其主要杂质的潜在神经毒性,为加强临床用药安全性提供参考。方法 利用在线数据库准备建模数据,分别采用人工神经网络和支持向量机算法构建2种不同原理的分类预测模型进行交互快速评价,并采用特征结构域初步探索毒性成因。结果 新建模型中,编号为ANN-3和SVM-2模型预测的假阳性、假阴性结果均小于4.0%,其灵敏度、准确性和稳健性良好;采用新建模型预测评估注射用左奥硝唑及3个主要杂质具有潜在神经毒性,可信度高于90%;特征结构域分析显示结构中羟基取代增加分子极性,是表现出潜在神经毒性的可能原因。结论 左奥硝唑及其主要杂质均表现出潜在神经毒性,需要密切关注注射剂在临床使用中的安全性;也为其他抗生素药物及其杂质的毒性快速识别与评价提供借鉴。

关键词: 计算模型, 数据库技术, 快速评价, 注射用左奥硝唑, 杂质潜在神经毒性

Abstract: Objective To quickly evaluate the potential neurotoxicity of levornidazole for injection and its main impurities so as to provide reference for safer clinical medications. Methods The modeling data were prepared using online databases. The artificial neural network and support vector machine algorithm were used to establish two classification prediction models with different principles for interactive rapid evaluation. The characteristic domain was used to explore the causes of toxicity. Results The false positive and false negative results of prediction of models numbered ANN-3 and SVM-2 were less than 4.0%, and these two models were highly sensitive, accurate and robust. The new models were used to predict and evaluate the potential neurotoxicity of levornidazole for injection and its three main impurities, and the reliability exceeded 90%. Analysis of the characteristic domain showed that hydroxyl substitution in the structure increased molecular polarity, which might account for its potential neurotoxicity. Conclusion Levononidazole and its main impurities show potential neurotoxicity, so we need to keep close watch on the safety of the injection in clinical use. This study is expected to provide reference for rapid identification and evaluation of the toxicity of other antibiotics and their impurities.

Key words: computational model, database technology, rapid evaluation, levornidazole for injection, potential neurotoxicity of impurities

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