Oxidative activation of linezolid to a reactive species: Implications for linezolid adverse drug reactions

Background Linezolid is a novel oxazolidone antimicrobial agent which is effective against gram positive bacteria. It is extensively metabolized. Serious adverse drug reactions to linezolid occur relatively frequently and can be life threatening. The mechanism of these and the potential role of metabolites is not known. Methods Linezolid was incubated in increasing concentrations and over increasing incubation times with Jurkat e6.1 lymphoblasts in the presence and absence of a murine microsomal activating system or a horseradish‐peroxidase (HRP) activating system. Viability was determined after incubation using a tetrazolium‐based assay. Results No toxicity was demonstrated with linezolid over a concentration range from 0 to 1200 μM in the absence of murine microsomes. In contrast, concentration‐dependent toxicity was demonstrated when cells were incubated in the presence of the HRP system (100±5% viability at 0μM, 20± 3% viability at 625 μM, p<0.05). At concentrations greater than 1000 μM, cell viability increased back towards baseline (80±5% at 1250 μM, p<0.05). Conclusion Oxidative activation of linezolid appears to produce metabolite(s) toxic to lymphoblasts not dependent on CYP450‐dependent metabolism. At high concentrations linezolid may act as an anti‐oxidant. This suggests that reactive linezolid metabolites may play a role in linezolid‐related adverse drug reactions. Clinical Pharmacology & Therapeutics (2005) 77 , P69–P69; doi: 10.1016/j.clpt.2004.12.157