Determination of the permeability characteristics of two sulfenamide prodrugs of linezolid across Caco-2 cells.

The purpose of this work was to study the permeability of two relatively lipophilic sulfenamide prodrugs of linezolid (clogP 0.85), N-(phenylthio)linezolid (1, clogP 2.77) and N-[(2-ethoxycarbonyl)ethylthio]linezolid (2, clogP 1.43), across Caco-2 cell monolayers. Both prodrugs were found to convert to linezolid in the donor compartment presumably from the reaction with free thiol groups on proteins on the surface of the Caco-2 cells, as no conversion was seen in the donor compartment media per se. Neither of the prodrugs could be detected in the receptor phase from either apical (AP) to basolateral (BL) or BL to AP studies. However, the appearance of linezolid in the receptor phase was biphasic with an initial rapid phase suggesting that the prodrugs were indeed more permeable, and for a short period, some prodrug was able to permeate in competition with conversion to linezolid on the donor phase surface. It appears that the prodrug was able to permeate was rapidly converted to linezolid prior to acceptor phase appearance. The second slower phase was due to the permeability of the donor-phase-formed linezolid, with the slopes similar to those from control experiments with linezolid. The limitations and possible utility of oral sulfenamide prodrugs are discussed. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3134–3141, 2012