Tissue distribution of dirithromycin: comparison with erythromycin.
In order to ensure effective in-vivo activity, high antibiotic concentrations need to be achieved rapidly at the site of the infection and effective post-dosage concentrations should be maintained. Dirithromycin, a new macrolide antibiotic, is converted in vivo to erythromycylamine, which has antimicrobial activity similar to that of the parent compound and a half-life of 20-50 h which allows for once-daily dosing. Both dirithromycin and erythromycylamine are released slowly from the tissue compartment and the major route of elimination is hepatic/faecal: approximately 10% of an oral dose is absorbed and rapidly leaves the circulation to localize in tissues. Dirithromycin and erythromycylamine achieve lung parenchyma concentrations of 1.58-3.81 mg/kg depending on the number of doses administered. Tissue concentrations are significantly higher than simultaneous serum concentrations. Studies in both healthy and pathological lung tissues have shown that significant antibiotic concentrations remain in the tissue 12 and 24 h post-dose. The presence of an inflammatory exudate, especially the phagocytic component, probably contributes to the increased local concentration of dirithromycin found in pathological tissues. The ability of macrolides to concentrate within phagocytes and alveolar macrophages accounts for the observed high lung tissue concentrations of dirithromycin. Dirithromycin also effectively penetrates bronchial secretions: concentrations of 1.04 mg/L 3 h and 1.3 +/- 1.5 mg/L 12 h after a single 250 mg dose. Following a single dose of 500 mg dirithromycin, bronchial mucosa concentrations of > 1.0 mg/kg were detected at 4-24 h post-dose; after multiple doses, concentrations increased to 1.30 mg/kg at 12 h post-dose. Single and multiple 500 mg doses resulted in mean nasal mucosa concentrations of 0.59 +/- 0.17 and 1.86 +/- 0.54 mg/kg (multiple dose) at 24 and 12 h, respectively. Administration of single oral doses of 500 mg 12 or 24 h before tonsillectomy resulted in 24 h post-dosing tonsillar concentrations of 0.60 +/- 0.55 mg/kg (56% of the 12 h concentrations) while doses of 1000 mg/day for two days, resulted in tonsillar antibiotic concentrations of 1.37 +/- 0.55 mg/kg which were maintained for 24 h after the last dose. Dirithromycin also penetrates prostatic tissue with concentrations of 4.1-6.5 mg/kg achieved 15-17 h after the second of two 500 mg doses. In conclusion, dirithromycin exhibits good tissue distribution within selected tissues, is rapidly distributed and persists in significant concentrations up to 24 h post-dose. These studies suggest that dirithromycin has an extremely large volume of distribution.
Bergogne-Bérézin
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Department of Microbiology, Bichat-Claude Bernard University-Hospital, Paris, France.
D000900:Anti-Bacterial Agents; D001980:Bronchi / Q000378:metabolism; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D008168:Lung / Q000378:metabolism; D018942:Macrolides; D009297:Nasal Mucosa / Q000378:metabolism; D014066:Palatine Tonsil / Q000378:metabolism; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D018942:Macrolides; C053853:dirithromycin; D004917:Erythromycin