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The accumulation of azithromycin in phagocytic cells was studied both in vitro by using a radiolabelled drug and a bioassay and in vivo for 12 volunteers receiving 1.5 g (total dose) orally within 3 days. In vitro, neutrophils and unfractionated blood leukocytes accumulated azithromycin up to 160-fold the extracellular concentration within 1 h at 37°C but less than 3-fold at 4°C. Dead cells accumulated up to 30-fold azithromycin, whereas NaF-treated celis accumulated up to 60-fold arithromycin. The mean efflux from preloaded cells was at most 31.0%O ± 10.6% (standard error of the mean) of the cell-associated concentration within 4 h of incubation at 37°C in drug-free buffer. In vivo, the azithromycin concentration was 45.2 + 6.1 mg/liter of intracellular fluid at 2 h after the third dose and 36.6 ± 8.3 mg/liter at 1 week thereafter. The corresponding concentrations in serum were 0.2 ± 0.1 (2 h) and <0.05 (1 week). The luminol-enhanced chemiluminescence response induced by phorbol myristate acetate, opsonized zymosan, and two opsonized strains ofHaemophilus influenzae (a type b capsulated strain and a noncapsulated strain) was also studied ex vivo by using the blood leukocytes from the 12 test volunteers and 4 control volunteers at 2 and 6 h after the third oral dose of azithromycin and at 2, 4, and 7 days thereafter. Azithromycin did not influence this response despite high levels of cellular accumulation.Azithromycin (CP-62, 993; XZ-450) is a new 15-membered macrolide with high tissue penetration (9) and in vitro activity against intracellular pathogens such as Legionella pneumophila and Chlamydia trachomatis (8,32). Macrolides are highly accumulated by phagocytic cells through at least two mechanisms: an energy-independent mechanism, which occurs even in dead cells or at 4°C and probably depends on pH and liposolubility (23), and an energy-dependent mechanism associated with the nucleoside transport system (22). Most of the intracellular drug is located in the cytoplasm (6). In vitro, the elution of the macrolides out of the phagocytes is very rapid (within minutes) once the extracellular drug is removed (13). Several investigators have shown that 14-membered macrolides can significantly impair oxidative metabolism of the neutrophils in vitro, as assessed by luminolenhanced chemiluminescence, superoxide generation, H202 and OH-production, and myeloperoxidase-mediated iodination of proteins (1,3,11,18,21). Inhibition occurred at fairly high concentrations (50 mg/liter for roxithromycin and erythromycin) and was reversible by washing the cells (18). Other antimicrobial agents have been shown to impair the oxidative metabolism of human polymorphonuclear leukocytes (PMN) investigated in vitro (11,21,31). Very few studies have questioned the in vivo relevance of these findings. Labro et al. (17) showed the opposite results when testing roxithromycin ex vivo (enhancing of oxidative mechanisms) by comparison with their in vitro studies (16,18). The mechanism of ex vivo enhancement of oxidative functions might be due...

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