Uptake and intracellular activity of ketolide HMR 3647 in human phagocytic and non-phagocytic cells

To evaluate the uptake of HMR 3647 into human neutrophils (PMNs), human peritoneal macrophages (PMOs) and tissue-cultured cells (epithelial cells and fibroblasts), and to assess the intracellular activity of this drug.

Cell uptake of HMR 3647 was measured by radiometric assay, as described by Klemper and Styrt. Intracellular activity was determined by incubation for 3 h of PMNs containing bacteria in the presence of HMR 3647.

The intracellular concentrations were 130 and 71 times higher than extracellular concentrations in PMNs and PMOs, respectively (extracellular concentrations: 2-25 mg/L). The cellular-to-extracellular concentration ratios (C/E) for tissue-cultured cells were lower than those obtained in phagocytic cells but still greater than 5. The uptake of HMR 3647 was rapid and non-saturable in all cells. HMR 3647 was released slowly from phagocytic cells. HMR 3647 (extracellular concentration: 0.5-10 mg/L) did not significantly reduce the intracellular survival rate of Staphylococcus aureus ATCC 25923 in PMNs.

HMR 3647 reaches intracellular concentrations several times higher than extracellular concentrations within phagocytic and non-phagocytic cells. The slow efflux of this drug from phagocytic cells suggests that these cells may be a vehicle for it, delivering it to sites of infection.