EFFECT OF BENZALKONIUM CHLORIDE EDTA ON THE OCULAR BIOAVAILABILITY OFKETOROLAC TROMETHAMINE FOLLOWING OCULAR INSTILLATION TO NORMAL AND DEEPITHELIALIZED CORNEAS OF RABBITS/

This study was designed to examine the effect of benzalkonium chloride /ethylenediaminetetraacetic acid (BAK/EDTA) on the ocular bioavailabil ity (F-ocular) of ketorolac tromethamine after ocular instillation to normal and de-epithelialized corneas of rabbits both in vitro and in v ivo. The in vitro F-ocular of the formulations was measured in flow-th rough perfusion chambers. For in vivo studies, a 35 mu L dose of 0.5% ketorolac tromethamine with or without BAK/EDTA was instilled into rab bit eyes with intact or de-epithelialized corneas. At 0.5, 1, 2, 4, 6, and 8 h postdose, rabbits were euthanized, and the corneas and aqueou s humor were collected from both eyes. The ketorolac concentrations fr om both in vivo and in vitro samples were quantified by reversed-phase high-performance liquid chromatography. The in vitro study results in dicated that BAK/EDTA statistically significantly increased the F-ocul ar of ketorolac through de-epithelialized corneas but not through inta ct corneas. The in vivo study results showed that BAK/EDTA had no effe ct on the F-ocular of ketorolac in rabbits with intact corneas, based on the values of the area under the aqueous humor concentration versus time curves (AUC(0-6h)) of ketorolac. AS expected, de-epithelializati on of the corneas produced a faster and greater ocular absorption of k etorolac as evidenced by the smaller T-max and larger AUC values compa red to those for the intact corneas in vivo. However, BAK/EDTA decreas ed the ocular absorption of ketorolac in rabbits with de-epithelialize d corneas. The half-lives (t(1/2)) of ketorolac in corneal tissue and aqueous humor were longer in rabbits with intact corneas than those in rabbits with de-epithelialized corneas. In conclusion, the in vivo F- ocular of ketorolac was not altered by BAK/EDTA in rabbits with intact corneas, but it was decreased by BAK/EDTA in rabbits with de-epitheli alized corneas. Therefore, the formulation with ketorolac alone may be better as a postoperative ocular analgesic.