Membrane transport of clindamycin in alveolar macrophages

Abstract

The use of antibiotics which can penetrate phagocytic cells and kill intracellular organisms is desirable in the treatment of chronic facultative bacterial infections. Recently, we reported that several antibiotics were selectively concentrated by rabbit alveolar macrophages. Clindamycin accumulation was especially marked. In the present study we evaluated the plasma membrane transport (initial uptake) of clindamycin in alveolar macrophages. The transport of clindamycin is an active process, as documented by requirements for cellular viability, elevated environmental temperature, metabolic energy, and establishment of the 40- to 50-fold cellular/extracellular gradient. Energy for membrane transport of the drug depended at least in part upon mitochondrial oxidative respiration and cell membrane Na-K pump activity. Kinetic analysis of active clindamycin transport revealed it to be saturable, with a high binding affinity (Km = 1 mM) and a high velocity of uptake (Vmax = 15.8 nmol/45 s per 10(6) cells). Clindamycin uptake was not influenced by the presence of hexose or amino acids, but was inhibited by nucleosides (adenosine, puromycin). Decreased clindamycin transport in the presence of puromycin was typical of competitive inhibition (increased Km, unchanged Vmax). Conversely, competitive inhibition of adenosine transport by clindamycin was documented. Thus, clindamycin is transported into alveolar macrophages via the nucleoside system. The potential biological consequences of this unique antibiotic transport mechanism are of interest.

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…Aminoglycosides accumulate slowly (over days in macrophages) by fluid-phase pinocytosis (296,355). Several specific membrane carriers for amino acids, nucleosides, and dipeptides have been suggested to play a role in the transport of ofloxacin (297) (although other authors did not confirm these results [291]), clindamycin (134), and ceftibuten in a nonphagocytic cell line (268). Similarly, glycoprotein 330 (gp330, megalin) mediates the uptake of various polybasic drugs including polymyxin B and aminoglycosides in epithelial cells (257).…”

Uptake and intracellular activity of sparfloxacin in human polymorphonuclear leukocytes and tissue culture cells

“…Sparfloxacin uptake by these cells was rapid and high. With extracellular concentrations of 2 mg/liter, the C/E ratios were higher than 4 after only 1 min of incubation for all types of cells.…”

“…Further studies to elucidate the mechanism of sparfloxacin uptake by PMN were performed as described previously (4). The importance of cell viability was studied by using PMN killed by exposure to 10% Formalin for 30 min.…”

Influence on Mitochondria and Cytotoxicity of Different Antibiotics Administered in High Concentrations on Primary Human Osteoblasts and Cell Lines

“…Macrolides and clindamycin like linezolid and chloramphenicol inhibit bacterial protein synthesis by binding the bacterial 50S ribosomal subunit and might inhibit mitochondrial protein synthesis as well, although this has not been shown directly so far (39). The impairment of mitochondrial energetics could also be caused by direct interaction with mitochondrial membranes, because at least macrolides are known to interact directly with phospholipids (35,47) and macrolides as well as clindamycin are accumulated intracellularly (22,48). The increase in lactate production caused by the fluoroquinolones was only marginal, because it was superposed with direct toxic effects in higher concentrations.…”