硝苯地平中杂质的遗传毒性(Q)SAR评价及Ames试验研究

Assessment of mutagenicity of impurities in nifedipine by(Q)SAR and Ames test

目的对硝苯地平中2个已知杂质进行遗传毒性(致突变性)评价。方法按照ICH M7指导原则的要求,采用基于专家知识规则的Derek和基于统计学的Sarah两类(Q)SAR评价系统,对硝苯地平的2个杂质进行评价和分类。对于(Q)SAR预测结果为阳性的杂质,进一步采用Ames试验进行验证。结果杂质Ⅰ、杂质Ⅱ预测结果为阳性,且分类为3类。杂质Ⅰ、杂质ⅡAmes试验中受试物40~5000μg/皿剂量范围内,在S9存在或不存在情况下,回复突变菌落数均未超过溶剂对照组菌落数的2倍,试验结果为阴性。结论杂质Ⅰ、杂质Ⅱ遗传毒性均为阴性,可以按照非遗传毒性杂质进行控制。

Aim To assess the mutagenicity of impurities in nifedipine.Methods According to ICH M7 guidelines,two(quantitative)structure-activity relationships[(Q)SAR]prediction methodologies,Derek(expert rule-based)and Sarah(statistical-based)were applied to assess and classify impurities in nifedipine(impurity 1 and impurity 2).Ames test was used to verify the mutagenicity of the impurities when they were predicted as positive.Results(Q)SAR evaluation results of impurity 1 and impurity 2 were positive,and they were classified as class 3.The results of Ames test indicated that the number of revertant colonies of test sample group was no more than twice of solvent control group and the test result represented negative at doses from 40 to 5000μg/plate with or without S9.Conclusions Impurity 1 and impurity 2 in nifedipine arenon-mutagenic,which can be controlled according to the non-heritage toxic impurities.