Time and concentration dependent influence of dirithromycin on neutrophilsoxidative burst

Dirithromycin is a 14-membered macrolide antibiotic, well known to yield hi gh intragranulocytic levels after several hour exposure. We chose therefore to investigate oxidative metabolism after prolonged incubation periods wit h neutrophils. Neutrophil generation of reactive oxygen species. represented by superoxide anion, was assessed after fMLP or Staphylococcus aureus-induced activation of the respiratory burst. Cellular uptake of the drug was assessed concurr ently, in order to attempt a correlation with time-dependent modifications of the cellular oxidative status. For 1 hour exposure time, a pro-oxidant effect was reported for lower conce ntrations, achievable during therapeutic administration, whereas the highes t ones promoted a potent anti-oxidant effect. After prolonged incubation ti mes, the anti-oxidant effect alone was reported, with time-dependent modifi cations of IC50 values. These values could be correlated with intracellular accumulation of the drug. The anti-inflammatory activity reported here for high dirithromycin concentrations, could be nevertheless clinically releva nt, since dirithromycin cellular uptake extends beyond 4 hours.