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

Objective 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 dr ug. Method Cell uptake of HMR 3647 was measured by radiometric assay, as descri bed by Klemper and Styrt. Intracellular activity was determined by incubati on for 3 h of PMNs containing bacteria in the presence of HMR 3647. Results The intracellular concentrations were 130 and 71 times higher than extracellular concentration in PMNs and PMOs, respectively (extracellular c oncentrations: 2-25 mg/L). The cellular-to-extracellular concentration rati os (C/E) for tissue-cultured cells were lower than those obtained in phagoc ytic cells but still greater than 5. The uptake of HMR 3647 was rapid and n on-saturable in all cells. HMR 3647 was released slowly from phagocytic cel ls. HMR 3647 (extracellular concentration: 0.5-10 mg/L) did not significant ly reduce the intracellular survival rate of Staphylococcus aureus ATCC 259 23 in PMNs. Conclusions HMR 3647 reaches intracellular concentrations several times hig her than extracellular concentrations within phagocytic and non-phagocytic cells. The slow efflux of this drug from phagocytic cells suggests chat the se cells may be a vehicle for it, delivering it to sites of infection.