Effect of benzalkonium chloride/EDTA on the ocular bioavailability of ketorolac tromethamine following ocular instillation to normal and de-epithelialized corneas of rabbits.
This study was designed to examine the effect of benzalkonium chloride/ethylenediaminetetraacetic acid (BAK/EDTA) on the ocular bioavailability (Focular) of ketorolac tromethamine after ocular instillation to normal and de-epithelialized corneas of rabbits both in vitro and in vivo. The in vitro Focular of the formulations was measured in flow-through perfusion chambers. For in vivo studies, a 35 microL dose of 0.5% ketorolac tromethamine with or without BAK/EDTA was instilled into rabbit 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 aqueous humor were collected from both eyes. The ketorolac concentrations from both in vivo and in vitro samples were quantified by reversed-phase high-performance liquid chromatography. The in vitro study results indicated that BAK/EDTA statistically significantly increased the Focular of ketorolac through de-epithelialized corneas but not through intact corneas. The in vivo study results showed that BAK/EDTA had no effect on the Focular of ketorolac in rabbits with intact corneas, based on the values of the area under the aqueous humor concentration versus time curves (AUC0-6h) of ketorolac. As expected, de-epithelialization of the corneas produced a faster and greater ocular absorption of ketorolac as evidenced by the smaller Tmax and larger AUC values compared to those for the intact corneas in vivo. However, BAK/EDTA decreased the ocular absorption of ketorolac in rabbits with de-epithelialized 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 Focular of ketorolac was not altered by BAK/EDTA in rabbits with intact corneas, but it was decreased by BAK/EDTA in rabbits with de-epithelialized corneas. Therefore, the formulation with ketorolac alone may be better as a post-operative ocular analgesic.
Department of Pharmacokinetics, Allergan, Inc., Irvine, CA 92713-9534, USA.
C
C
Madhu
P J
PJ
Rix
M J
MJ
Shackleton
T G
TG
Nguyen
D D
DD
Tang-Liu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001548:Benzalkonium Compounds / Q000494:pharmacology*; D001682:Biological Availability; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism; D004337:Drug Carriers; D004492:Edetic Acid / Q000494:pharmacology*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006207:Half-Life; D020911:Ketorolac Tromethamine; D009883:Ophthalmic Solutions; D011817:Rabbits; D014046:Tolmetin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014325:Tromethamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001548:Benzalkonium Compounds; D004337:Drug Carriers; D009883:Ophthalmic Solutions; D014325:Tromethamine; D020911:Ketorolac Tromethamine; D004492:Edetic Acid; D014046:Tolmetin