Abstract
Linezolid has been widely used in serious infections for its effective inhibiting effect against multidrug-resistant gram-positive pathogens. However, linezolid caused severe adverse reactions, such as thrombocytopenia, anaemia, optic neuropathy, and near-fatal serotonin syndrome. In order to investigate the toxicity of linezolid, twenty-four Sprague-Dawley rats were randomly divided into: control group (n=7), low-group (n=8), and high-group (n=9). The rats of low-group and high-group were given by gavage with linezolid 60 and 120 mg/kg/day for 7 days, respectively. The serum concentration of linezolid was determined by high performance liquid chromatography (HPLC); blood metabolic change was analyzed by gas chromatography-mass spectrometer (GC-MS). Adenosine triphosphate (ATP) concentration in HepG2-C3A after being cultured with linezolid was determined by HPLC. The results showed that there were six metabolites and nine metabolites had statistical differences in low-group and high-group (P<0.05). The trimethyl phosphate was the most significant indicator in those changed metabolites. Except for d-glucose which was slightly increased in low-group, octadecanoic acid, cholest-5-ene, hexadecanoic acid, α-linolenic acid, eicosapentaenoic acid, 9,12-Octadecadienoic acid, and docosahexaenoic acid were all decreased in low-group and high-group. ATP concentration was decreased in HepG2-C3A after cultured with linezolid. In conclusion, the toxicity of linezolid is related to its serum concentration. Linezolid may inhibit the synthesis of ATP and fatty acid.
Highlights
Linezolid, the first approved synthetic oxazolidinone, is active against multidrug-resistant gram-positive pathogens, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant staphylococcus aureus (MRSA), several anaerobes, Nocardia species, and some mycobacteria [1,2,3,4]
We firstly investigated the effect of linezolid on blood metabolic changes in rat by gas chromatography-mass spectrometer (GC-MS)
The limit of detection was 0.05 μg/mL when S/N was 1/10. The validation of this method showed that the relative standard deviations (RSD) of each quality control (QC) sample (0.5, 5, and 15 μg/mL) for intraday and interday precision were all less than 10%; the recovery of linezolid was higher than 70% (Table 1)
Summary
The first approved synthetic oxazolidinone, is active against multidrug-resistant gram-positive pathogens, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant staphylococcus aureus (MRSA), several anaerobes, Nocardia species, and some mycobacteria [1,2,3,4]. Linezolid has a lower mortality than daptomycin in treatment for VRE bacteremia [5]. It is a viable option in the treatment of multidrug-resistant or extensively drugresistant tuberculosis [6]. Linezolid induced toxic optic neuropathy [13], near-fatal serotonin syndrome [14], and acute interstitial nephritis [8]. Those toxic effects always occur more frequently in patients who receive linezolid for two weeks or more long time. The exact mechanism of its toxicity still remains unclear
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