Objective: To evaluate the genotoxicity of an impurity in bromhexine hydrochloride and provide a toxicological basis for the establishment of reasonable limits. Methods: The impurity N-(2-nitro)-N-cyclohexylN-methylamine was classified using Derek (expertise-based) and Sarah's (statistics-based) quantitative structureactivity relationship ((Q)SAR) method according to the requirements of the Chinese Pharmacopoeia and the ICH M7 guidelines. The prediction results were verified by mini-Ames test, and the classification and a reasonable limit of the impurity were subsequently accurately determined. Results: N-(2-nitro)-N-cyclohexyl-N-methylamine was classified as Class 3 impurities according to (Q)SAR prediction. The result of the Mini-Ames test showed that N-(2-nitro)-N-cyclohexyl-N-methylamine did not increase the number of revertants in each group with or without the activation system, and the results of the mini-Ames test were negative. Conclusion: N-(2-nitro)-N-cyclohexylN-methylamine was non-genotoxicitic and its limit could be defined as common impurities.
Li Rui, Zhou Su, Zhu Hongyan, Zhang Zhichao, Fang Jing, Gu Minyang, Ji Zhiwen, Tang Liming
. Genotoxicity Evaluation of the Impurity N-(2-nitro)-N-cyclohexyl-Nmethylamine in Bromhexine Hydrochloride[J]. Chinese Pharmaceutical Affairs, 2021
, 35(9)
: 1024
-1028
.
DOI: 10.16153/j.1002-7777.2021.09.009
[1] 王涛,吴桂芝,董铎.盐酸溴己新注射剂安全性风险的分析及思考[J].中国药物警戒,2019,16(3):171-173+178.
[2] 江莹,漆建军,李田,等.208例盐酸溴己新注射剂不良反应报告分析[J].药物流行病学杂志,2020,29(8):544-548.
[3] 汪磊.国家药品评价性抽验管理制度研究[D].沈阳:沈阳药科大学,2015.
[4] Flamand N,Meunier J,Meunier P,et al.Mini Mutagenicity Test:a Miniaturized Version of the Ames Test Used in a Prescreening Assay for Point Mutagenesis Assessment[J].Toxicol In Vitro,2001,15(2):105-114.
[5] OECD.Test No.471:Bacterial Reverse Mutation Test[S].1997.
[6] Maron D M,Ames B N.Revised Methods for the Salmonella Mutagenicity Test[J].Mutat Res,1983,113(3-4):173-215.
[7] Zeiger E.Reflections on a Career and on the History of Genetic Toxicity Testing in the National Toxicology Program[J].Mutation Research,2017,773:282-292.
[8] ICH M7:ICH Quality Guidelines[S].2017:667-699.
[9] 文海若,闫明,王亚楠,等.药物杂质遗传毒性评价策略与监管研究[J].中国药事,2020,34(2):131-140.
[10] 中华人民共和国药典:四部[S].2020:通则9306遗传毒性杂质控制指导原则.
[11] Wichard J D.In Silico Prediction of Genotoxicity[J].Food Chem Toxicol,2017,106(Pt B):595-599.
[12] Zhu Q,Li T,Li J,et al.In Silico and in Vitro Genotoxicity Evaluation of Levofloxacin n-oxide,an Impurity in Levofloxacin[J].Toxicol Mech Methods,2012,22(3):225-30.
[13] Honma M,Kitazawa A,Cayley A,et al.Improvement of Quantitative Structure-activity Relationship(QSAR)Tools for Predicting Ames Mutagenicity:Outcomes of the Ames/QSAR International Challenge Project[J].Mutagenesis,2019,34(1):3-16.
[14] Egorova O V,Ilyushina N A,Rakitskii V N.Mutagenicity Evaluation of Pesticide Analogs Using Standard and 6-well Miniaturized Bacterial Reverse Mutation Tests[J].Toxicol In Vitro,2020,69:105006.
