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

Abstract

Determination of clarithromycin (CL) and azithromycin (AZ) uptake by human polymorphonuclear leukocytes (PMNs), monocytes and alveolar macrophages showed that AZ achieved higher levels than CL. The uptake kinetics of AZ were time-dependent over an 18 h 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 24 h 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.

Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis

“…Spontaneous degradation and impaired transport of clarithromycin across the capillary barrier is unlikely to account for the observation reported above because (i) clarithromycin is highly stable and (ii) the high density of negative charges in the basement membrane of the capillary endothelium should facilitate the diffusion of lipophilic basic drugs to the extracellular-space fluid (12). Probably, fast and high-level intracellular uptake of clarithromycin into lysosomes, likely assisted by a phenomenon called "ion-trapping," is one explanation for the unexpectedly low concentrations of clarithromycin in the interstitium (5,9). The elimination half-life of clarithromycin in tissues and plasma was about 2 h in our study collective after a single dose of 250 mg. As observed previously in other studies (7,22), a nonlinear plasma and tissue pharmacokinetic profile of clarithromycin was detected following administration of the higher dose of 500 mg twice a day in a 12-h interval ( Table 2).…”

“…High tissue concentrations of the class of the macrolides have been reported previously in the literature (10,13,21). Indeed, intracellular accumulation of macrolides in isolated peripheral blood phagocytes, alveolar macrophages, and tissue culture cells of human origin has been demonstrated previously (9,16). To date, investigations of in vivo tissue pharmacokinetics (PK) of clarithromycin have been confined to concentrations derived from homogenized biopsy samples of the upper and lower respiratory tract and epithelial lining fluid collection obtained by bronchoalveolar lavage (10,13,21).…”

Disposition and intracellular levels of moxifloxacin in human THP-1 monocytes in unstimulated and stimulated conditions

“…Secondly, at pH 5 the integrity of the plasma membrane may be damaged leading to leakage of the moxifloxacin from the cells. Decreased uptake of macrolides at lower pH has previously been observed in PMNs, fibroblasts and monocytes [4,7,8,13,19,20]. The cellular/extracellular [C/E] ratios of 200 for azithromycin in PMNs [6] and 61 in fibroblast [7] led these investigators to predict that these cells could transport the antibiotic through out the body to fight infection [7,20].…”

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

“…19 In fact, the use of drugs with a wellestablished safety profile and for which the target in humans has been already validated allows to drastically reduce the rate of clinical trial failure that has dominated the unsuccessful development of neuroprotective drugs in stroke during the past decades. [19][20][21] Following the concept of drug repurposing, with the aim of exerting a rational immunomodulation, we have recently validated the preclinical efficacy of azithromycin (9-deoxy9a-aza-9a-methyl-9a-homoerythromycin A), a dibasic macrolide antibiotic that accumulates in macrophages and neutrophils [22][23][24] and displays prolonged antibacterial as well as anti-inflammatory and immunomodulatory effects. 25 Acute intraperitoneal (i.p.)…”