氯唑沙宗杂质的遗传毒性研究

Study on Genotoxicity of Clozoxazone Impurities

目的:本试验在体外条件下研究氯唑沙宗杂质是否具有遗传毒性,为临床用药安全提供依据。方法:采用Derek和Sarah方法,从定量构效关系(Q)SAR的角度对氯唑沙宗杂质进行分类和评价。对于软件预测结果为阳性的杂质,进一步采用细菌回复突变试验验证上述结果。结果:氯唑沙宗杂质6(CAS:889884-60-0)、杂质7(CAS:28443-50-7)的Derek和Sarah软件预测结果为阳性。细菌回复突变试验中,杂质6、杂质7在15~1250μg/皿剂量范围内,在代谢活化系统S9存在或不存在的情况下,五种菌株的回变菌落数均未超过自发回变菌落数2倍以上,试验结果为阴性。结论:氯唑沙宗杂质6、杂质7体外细菌回复突变试验结果均为阴性,可以按照非遗传毒性杂质进行控制。

Objective:This study was conducted to investigate the genotoxicity of known impurities in clozoxazone in vitro,and to provide evidence for clinical drug safety.Methods:The methods of Derek and Sarah were used to classify and evaluate clozoxazone impurities from the aspect of quantitative structure-activity relationship(Q)SAR.Reverse mutation were further used to verify those impurities predicted as positive.Results:Impurity 6 and impurity 7 were predicted by Derek and Sarah methods as positive.In the bacterial reverse-mutation tests of five strains,the results of impurity 6 and impurity 7 were negative,their numbers of reverse mutation colonies did not exceed twice those number of spontaneous reverse-mutation colonies,in the dose range of 15-1250μg/plate with or without S9.Conclusion:Clozoxazone impurity 6 and impurity 7 are negative candidates of bacterial reverse mutation,and can be controlled as non-genotoxic impurities.