In silico and in vitro genotoxicity evaluation of levofloxacin n-oxide, an impurity in levofloxacin.

Abstract:

: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.

journal_name

Toxicol Mech Methods

authors

Zhu Q,Li T,Li J,Guo M,Wang W,Zhang X

doi

10.3109/15376516.2011.635319

subject

Has Abstract

pub_date

2012-04-01 00:00:00

pages

225-30

issue

3

eissn

1537-6516

issn

1537-6524

journal_volume

22

pub_type

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