摘要
目的基于计算机模型和体外毒性试验研究兰索拉唑相关杂质的遗传毒性。方法通过对兰索拉唑已知杂质进行(定量)构-效关系[(Q)SAR]计算机毒理学预测及斑马鱼胚胎发育毒性比较,选择胚胎毒性最强的兰索拉唑氯化物(lansoprazole chloride)进行细菌回复突变试验;通过液质联用技术,使用ACE Excel 3AQ(2.1 mm×100 mm)C_(18)色谱柱,流动相体积分数0.1%甲酸(A)-甲醇(B),梯度洗脱,质谱采用电喷雾离子源(electrospray ionization,ESI),多反应监测(multiple reaction monitoring,MRM)正离子模式,对全国12个企业的原料药或制剂进行兰索拉唑氯化物分析。结果杂质兰索拉唑氯化物计算机预测结果阳性,在兰索拉唑相关杂质中斑马鱼胚胎毒性最强且细菌回复突变(Ames)试验结果阳性,在部分企业原料药及相关制剂中检出。结论本研究验证了兰索拉唑相关杂质中兰索拉唑氯化物具有遗传毒性,并采用液质联用技术在部分兰索拉唑原料药及制剂中有所检出,为兰索拉唑原料药及制剂的质量控制提供了实验依据。
OBJECTIVE To study the genotoxicity of lansoprazole′s related impurities based on computer models and in vitro toxicity tests.METHODS After(Q)SAR computer toxicology prediction of known impurities of lansoprazole and comparison of the embryonic developmental toxicity of zebrafish,lansoprazole chloride was selected for bacterial reversion test.Gradient elution was carried out on an ACE Excel 3AQ(2.1 mm×100 mm)C_(18) column with 0.1%formic acid as mobile phase A and methanol as mobile phase B.Multiple reaction monitoring(MRM)was conducted in positive ion mode using electrospray ion source(ESI)interface.Mass transitions m/z 240.1→106.1 and m/z 240.1→204.1 were set as quantitative and qualitative ion pairs.Lansoprazole chloride analysis was performed on APIs or preparations from 12 enterprises nationwide.RESULTS Lansoprazole chloride was positive in the Q(SAR)toxicity prediction,showed the highest embryotoxicity among the related purities in the zebrafish test,with positive result for the AMES test.Lansoprazole chloride was detected in some APIs and related preparations.CONCLUSION In this study,lansoprazole chloride is verified to be genotoxic,and it is detected in APIs and related preparations by LC-MS/MS technology,which provides an experimental basis for the quality control of lansoprazole APIs and preparations.
作者
张倩
申芸
赵恂
张锐
张靖溥
袁耀佐
陈民辉
张锦琳
ZHANG Qian;SHEN Yun;ZHAO Xun;ZAHNG Rui;ZHANG Jingpu;YUAN Yaozuo;CHEN Minhui;ZHANG Jinlin(NMPA Key Laboratory for Impurity Profile of Chemical Drug,Jiangsu Institute for Food and Drug Control,Nanjing 210019,China;China Pharmaceutical University,Nanjing 211121,China;Institute of Medical Biotechnology,Chinese Academy of Medical Sciences,Beijing 100021,China)
出处
《中国药学杂志》
CAS
CSCD
北大核心
2023年第23期2165-2171,共7页
Chinese Pharmaceutical Journal
作者简介
共同第一作者:张倩,女,硕士研究生,主管药师,研究方向:药物分析;共同第一作者:申芸,女,硕士研究生,研究方向:药物分析;通信作者:张锦琳,女,主任药师,研究方向:药物分析,Tel:(025)86251131。
