Requirements for Intracellular Accumulation and Release of Clarithromycin and Azithromycin by Human Phagocytes

Abstract

Determination of clarithromycin (CL) and azithromycin (AZ) uptake by human polymor-phonuclear leukocytes (PMNs), monocytes and alveolar macrophages showed that AZ achieved higher levels than CL. The uptake kinetics of AZ were time-dependent over an 18h period, while those of CL were similar to erythromycin (ER) kinetics, with a maximum level of incorporation being obtained after a 60 min incubation. The accumulation of both drugs was influenced by extracellular antibiotic-concentrations, PMN viability, extracellular calcium, physiological environmental temperature and pH. The uptake was not modified by inhibitors of cell metabolism or activators of cell membranes. After removal of extracellular antibiotic, the release of AZ from PMNs was very slow: nearly 50% of the drug remained cell-associated after 24h incubation. The efflux of this derivative was significantly enhanced when drug-loaded PMNs were stimulated by phorbol-myristate acetate (PMA). The kinetics of CL release indicated that this macrolide behaved like ER. Nevertheless, about 10% of the initial cell-associated antibiotic showed a prolonged retention. On the whole, these data suggest that diffusion through cell membranes and trapping into acidic compartments of PMNs are important events in CL and AZ uptake.