Stereoselective permeation of new fluorinated quinolone derivatives across LLC-PK1 cell monolayers

We examined the stereoselective membrane permeation of new fluorinated quinolone derivatives (NQs) across LLC-PK1 cell monolayers, using levofloxacin (LVFX) and its R-(+) isomer. LVFX permeation was 1.6-fold greater in the basal-to-apical direction than that in the apical-to-basal direction, suggesting that LVFX permeated LLC-PK1 cell monolayers in a secretory-oriented manner. In contrast to LVFX, the permeation of the R-(+) isomer was almost identical in both directions. LVFX permeation in the basal-to-apical direction was significantly reduced in the presence of guanidine, enoxacin, and L-arginine, whereas tetraethylammonium, D-arginine, D- and L-lysine had no effect on the basal-to-apical permeation of LVFX. Basal-to-apical permeation of the R-(+) isomer was not affected by these compounds. Cellular accumulation of LVFX was inversely increased when guanidine suppressed the appearance of LVFX in the apical medium in a concentration-dependent manner. These results imply that the inhibitory effect of guanidine on the basal-to-apical permeation of LVFX involves the permeation process across the apical membrane. Guanidine trans-stimulated the efflux of LVFX from LLC-PK1 cells but did not affect cimetidine efflux. These results suggest that some NQs, like LVFX and its R-(+) isomer, are stereoselectively secreted across LLC-PK1 cell monolayers and that an organic cation transport system, which favors guanidine as a typical substrate, may be involved in the secretory-oriented permeation of some NQs.