1. Antimicrob Agents Chemother. 2010 Jun;54(6):2540-8. Epub 2010 Apr 12.

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

Lemaire S, Tulkens PM, Van Bambeke F.

Unité de Pharmacologie cellulaire et moléculaire, Université catholique de
Louvain, Brussels, Belgium.

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 the 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-lives of approximately 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 was
reduced to 20 to 30% of control values for cells in medium at a pH of <6 or in
the presence of monensin, which collapses pH gradients between the extracellular 
and intracellular compartments). The accumulation at equilibrium was not affected
by efflux pump inhibitors (verapamil and gemfibrozil) and was markedly reduced at
4 degrees C but was further increased in medium 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.

PMID: 20385873 [PubMed - in process]