Cellular pharmacokinetics of the novel biaryloxazolidinone radezolid in phagocytic cells : studies with macrophages and polymorphonuclear neutrophils

Lemaire, Sandrine [UCL] Tulkens, Paul M. [UCL] Van Bambeke, Françoise [UCL]

Radezolid (RX-1741) is the first biaryloxazolidinone in clinical development. It shows improved activity, including against linezolid-resistant strains. Radezolid differs from linezolid by the presence of a biaryl spacer and of a heteroaryl side chain, which increases the ionization and hydrophilicity of the molecule at physiological pH and confers to it a dibasic character. The aim of this study was to determine accumulation and subcellular distribution of radezolid in phagocytic cells and to decipher the underlying mechanisms. In THP-1 human macrophages, J774 mouse macrophages, and human polymorphonuclear neutrophils, radezolid accumulated rapidly and reversibly (half-life of approx. 6 min and 9 min for uptake and efflux, respectively) to reach at equilibrium a cellular concentration 11-fold higher than the extracellular one. This process was concentration- and energy-independent, but pH-dependent (accumulation reduced to 20-30 % of control values for cells in medium at pH < 6 or in the presence of monensin [collapsing pH gradients between the extracellular and intracellular compartments]). Accumulation at equilibrium was not affected by efflux pumps inhibitors (verapamil, gemfibrozil) and markedly reduced at 4 degrees C, but was further increased in media with low serum content. Subcellular fractionation studies demonstrated a dual subcellular distribution for radezolid, with approximately 60 % of the drug colocalizing to the cytosol and approximately 40 % to the lysosomes, with no specific association with mitochondria. These observations are compatible with a mechanism of transmembrane diffusion of the free fraction and partial segregation of radezolid in lysosomes by proton trapping, as previously described for macrolides.