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Antimicrob Agents Chemother. 1994 July; 38(7): 1548-1554

Effects of dirithromycin and erythromycylamine on human neutrophil degranulation.

H Abdelghaffar, E M Mtairag and M T Labro

INSERM U294, CHU Xavier Bichat, Paris, France.

ABSTRACT

Dirithromycin and, to a lesser extent, erythromycylamine and erythromycin directly induced the release of three intragranular enzymes (lysozyme, lactoferrin, and beta-glucuronidase) from unstimulated human neutrophils. Macrolide-induced enzyme release was dependent upon the incubation time (30 to 180 min) and drug concentration. Dirithromycin was the most effective. At 120 min, release of lysozyme, beta-glucuronidase, and lactoferrin by macrolide (100 micrograms/ml)-treated cells, expressed as a percentage of total enzyme content, was, respectively, 58% +/- 8.3%, 52% +/- 10.7%, and 35% +/- 5.1% (dirithromycin); 42% +/- 3.9%, 28% +/- 5.8%, and 10% +/- 2.2% (erythromycylamine); and 35% +/- 4.0%, 19% +/- 4.3%, and 10% +/- 5.2% (erythromycin) (mean +/- standard error of the mean of three to eight experiments). The lowest macrolide concentrations which induced significant enzyme release were 10, 100, and 25 micrograms/ml, respectively, for dirithromycin, erythromycylamine, and erythromycin. Furthermore, we obtained evidence of a link between the prodegranulation effects of dirithromycin and erythromycylamine and the intragranular location of these drugs. Indeed, cell-associated drug levels increased for up to 60 min and then plateaued and declined substantially. Increasing the pH from 7 to 9 resulted in a parallel increase in drug uptake and the prodegranulation effect. Finally, when macrolide-treated neutrophils were disrupted by sonication and centrifuged, a correlation was found between lysozyme and beta-glucuronidase activities (both granule markers) and pellet-associated macrolide levels. Taken together, our results suggest that dirithromycin and erythromycylamine concentrate within neutrophil granules and then induce degranulation.

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Antimicrob Agents Chemother. 1994 July; 38(7): 1548-1554

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