Department of Pharmacology, Shandong University, School of Medicine, Jinan, Shandong, PR China.
Toxicol Mech Methods. 2012 Apr;22(3):225-30. doi: 10.3109/15376516.2011.635319. Epub 2011 Nov 16.
Impurities in drug substances and drug products generally do not have beneficial effects and may impose a risk without associated benefit. Levofloxacin n-oxide is an impurity isolated from levofloxacin. However there is insufficient toxic information about levofloxacin n-oxide. This study investigates the genotoxicity of this impurity by in silico and in vitro methods. We used Derek, a commercial structure-activity relationship software package as an in silico tool. The results showed that there was a structural alert (quinolone-3-carboxylic acid or naphthyridine analogue) in this impurity. Then the mouse lymphoma assay (MLA) and chromosome aberration assay in Chinese hamster lung (CHL) cells were conducted in vitro. Both assays were conducted in the presence or absence of S-9 mix. The test impurity was not mutagenic in the test of MLA. While there was a statistically significant increase in the number of metaphase CHL cells with structural aberrations at the concentration of 1 mg/mL with S-9 mix, and the aberrations rate is 6.5%. It did not significantly increase the number of structural aberration in CHL cells in the presence (at other two doses) or absence of S-9 mix. Based on these assays, levofloxacin n-oxide could be controlled as a non-genotoxic impurity despite the DEREK alert for quinolone-3-carboxylic acid or naphthyridine analogue.
杂质在药物物质和药物产品中一般没有有益的效果，而且可能带来风险而没有相关的益处。左氧氟沙星 n-氧化物是从左氧氟沙星中分离出来的杂质。然而，关于左氧氟沙星 n-氧化物的毒理信息还不够充分。本研究通过体内和体外方法研究了这种杂质的遗传毒性。我们使用了 Derek，一种商业结构-活性关系软件包作为体内工具。结果表明，这种杂质中存在结构警报（喹诺酮-3-羧酸或萘啶类似物）。然后在体外进行了小鼠淋巴瘤试验（MLA）和中国仓鼠肺（CHL）细胞染色体畸变试验。这两个试验都在有或没有 S-9 混合物的情况下进行。在 MLA 试验中，测试杂质没有致突变性。然而，在有 S-9 混合物的情况下，浓度为 1mg/mL 时，中期 CHL 细胞的结构异常数量有统计学上的显著增加，并且异常率为 6.5%。在有 S-9 混合物（在其他两个剂量下）或没有 S-9 混合物的情况下，CHL 细胞中结构异常的数量没有显著增加。基于这些试验，尽管 DEREK 对喹诺酮-3-羧酸或萘啶类似物发出警报，但可以将左氧氟沙星 n-氧化物控制为非遗传毒性杂质。
