title: Characterization of the carrier-mediated transport of levofloxacin, a fluoroquinolone antimicrobial agent, in rabbit cornea.
abstract: The cornea presents a formidable barrier to drug penetration. The fluoroquinolone levofloxacin, which is an effective antimicrobial agent, has the potential to be used in the topical treatment of ocular disease. Thus, we sought to characterize how levofloxacin penetrates the cornea. To perform this characterization, we measured the time dependent permeation of levofloxacin across the isolated rabbit cornea using a diffusion chamber, and compared it with antipyrine fluxes. Levofloxacin permeation into the receiver epithelial-side bathing solution (pH = 6.5) from the donor endothelial-side (pH = 7.4) reached 3.00 nmolcm(-2) cornea after 2h, whereas in the opposite direction permeation was 1.89 nmolcm(-2) cornea. Based on the temperature-dependent effects on permeation, the calculated energy of activation for permeation, Ea, was 31.3 kcal mol(-1), whereas Ea for antipyrine, a marker of diffusion, was 11.0 kcalmol(-1). The transport of levofloxacin from epithelium to endothelium was concentration-dependent and had both a linear and saturable component. Evaluation of the kinetic parameters, Jmax, apparent Km and k(d) showed that they were 38.78 pmol min(-1) cm(-2), 3.83 mM and 0.0135 microL min(-1) cm(-2), respectively. These results, coupled with the fact that levofloxacin permeation reached a maximum value at pH 6.5, suggest that levofloxacin transport across the cornea is carrier mediated. However, at present, it cannot be ascertained whether such a system is localized in either the corneal epithelial or the endothelial layer.
authors.affiliation: Santen Pharmaceutical Co. Ltd, Nara Research and Development Center, Ophthalmic Research Division, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawazu
authors.forename: Y
authors.initials: Y
authors.lastname: Midori
authors.forename: H
authors.initials: H
authors.lastname: Shiono
authors.forename: A
authors.initials: A
authors.lastname: Ota
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D003315:Cornea / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D064704:Levofloxacin; D008297:Male; D015242:Ofloxacin / Q000493:pharmacokinetics*; D010539:Permeability; D011817:Rabbits; D013696:Temperature
chemical_list: D000890:Anti-Infective Agents; D002352:Carrier Proteins; D064704:Levofloxacin; D015242:Ofloxacin