Levert H, Gressier B, Brunet C, Dine T, Luyckx M, Ballester L, Templier F, Cazin M, Cazin J C
Laboratoire de Pharmacologie, Pharmacocinétique et Pharmacie Cliníque, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
J Antibiot (Tokyo). 1999 Feb;52(2):127-33. doi: 10.7164/antibiotics.52.127.
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.
地红霉素是一种14元大环内酯类抗生素，众所周知，在接触数小时后会在粒细胞内产生较高水平。因此，我们选择研究与中性粒细胞长时间孵育后的氧化代谢。在用fMLP或金黄色葡萄球菌诱导呼吸爆发激活后，评估以超氧阴离子为代表的中性粒细胞活性氧的产生。同时评估药物的细胞摄取，以试图与细胞氧化状态的时间依赖性变化建立关联。在1小时的暴露时间内，较低浓度（治疗给药期间可达到）表现出促氧化作用，而最高浓度则促进强效抗氧化作用。延长孵育时间后，仅报告了抗氧化作用，IC50值随时间变化。这些值可能与药物在细胞内的积累有关。尽管如此，这里报道的高地红霉素浓度的抗炎活性可能具有临床相关性，因为地红霉素的细胞摄取会持续超过4小时。
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