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Time and concentration dependent influence of dirithromycin on neutrophils oxidative burst
H Levert1, B Gressier, C Brunet
1Laboratoire de Pharmacologie, Pharmacocinétique et Pharmacie Cliníque, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
Abstract:
Dirithromycin is a 14-membered macrolide antibiotic, well known to yield high intragranulocytic levels after several hour exposure. We chose therefore to investigate oxidative metabolism after prolonged incubation periods with 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 concurrently, 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 concentrations, achievable during therapeutic administration, whereas the highest ones promoted a potent anti-oxidant effect. After prolonged incubation times, the anti-oxidant effect alone was reported, with time-dependent modifications 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 relevant, since dirithromycin cellular uptake extends beyond 4 hours.
Insights
Dirithromycin exhibits dual effects on neutrophil oxidative metabolism, acting as a pro-oxidant at low concentrations and an antioxidant at high concentrations. Prolonged exposure to dirithromycin primarily results in antioxidant effects, potentially offering clinical anti-inflammatory benefits.
Area of Science:
- Pharmacology
- Immunology
- Microbiology
Background:
- Dirithromycin, a macrolide antibiotic, achieves high intracellular concentrations in neutrophils.
- Understanding its impact on neutrophil oxidative metabolism is crucial for clinical applications.
Purpose of the Study:
- To investigate the oxidative metabolism of neutrophils following prolonged dirithromycin exposure.
- To correlate cellular drug uptake with time-dependent changes in oxidative status.
Main Methods:
- Neutrophil activation using fMLP or Staphylococcus aureus to induce respiratory burst.
- Assessment of reactive oxygen species (superoxide anion) generation.
- Concurrent measurement of intracellular dirithromycin accumulation.
Main Results:
- At 1-hour exposure, low dirithromycin concentrations showed pro-oxidant effects, while high concentrations exhibited antioxidant effects.
- Prolonged incubation (beyond 1 hour) consistently demonstrated antioxidant effects.
- IC50 values for antioxidant effects changed over time and correlated with intracellular drug levels.
Conclusions:
- Dirithromycin's oxidative effects are concentration- and time-dependent.
- The observed antioxidant and anti-inflammatory potential of dirithromycin at high concentrations may be clinically relevant due to its sustained cellular uptake.