title: Stereoselective permeation of new fluorinated quinolone derivatives across LLC-PK1 cell monolayers.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sasaya
authors.forename: Y
authors.initials: Y
authors.lastname: Hatakeyama
authors.forename: H
authors.initials: H
authors.lastname: Saitoh
authors.forename: M
authors.initials: M
authors.lastname: Takada
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D002412:Cations / Q000378:metabolism; D002463:Cell Membrane Permeability; D002927:Cimetidine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019791:Guanidine / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D018374:LLC-PK1 Cells; D064704:Levofloxacin; D008353:Mannitol / Q000493:pharmacokinetics; D015242:Ofloxacin / Q000737:chemistry / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013552:Swine; D014316:Tritium
chemical_list: D000890:Anti-Infective Agents; D002412:Cations; D014316:Tritium; D008353:Mannitol; D064704:Levofloxacin; D002927:Cimetidine; D015242:Ofloxacin; D019791:Guanidine