Ocular penetration and anti-inflammatory activity of ketorolac 0.45% and bromfenac 0.09% against lipopolysaccharide-induced inflammation

J Ocul Pharmacol Ther. 2011 Apr;27(2):173-8. doi: 10.1089/jop.2010.0135. Epub 2011 Feb 25.

Abstract

Purpose: Anti-inflammatory activity of topical nonsteroidal anti-inflammatory drugs is mediated by suppression of cyclooxygenase (COX) isoenzymes. This study compared ocular penetration and inflammation suppression of topical ketorolac 0.45% and bromfenac 0.09% ophthalmic solutions in a rabbit model.

Methods: At hour 0, 36 rabbits received ketorolac 0.45%, bromfenac 0.09%, or an artificial tear 3 times once every 20 min. Half of the rabbits in each group then received intravenous injections of lipopolysaccharide (LPS) and fluorescein isothiocyanate (FITC)-dextran at hour 1, and the other half at hour 10. Aqueous and iris-ciliary body (ICB) samples were collected in the former group at hour 2 (peak) and in the latter group at hour 11 (trough) An additional group of 6 animals received only FITC-dextran, and samples were collected 1 h later. Peak and trough nonsteroidal anti-inflammatory drug concentrations were compared with previously determined half-maximal inhibitory concentrations (IC(50)) for COX isoenzymes.

Results: Peak and trough aqueous and ICB concentrations of ketorolac were at least 7-fold or greater than those of bromfenac. At peak levels, both ketorolac 0.45% and bromfenac 0.09% significantly inhibited LPS-induced aqueous prostaglandin E(2) and FITC-dextran elevation (P < 0.01). At trough, both study drugs significantly inhibited LPS-induced aqueous prostaglandin E(2) elevation (P < 0.05), but only ketorolac 0.45% significantly reduced LPS-induced aqueous FITC-dextran elevation (P < 0.01). Aqueous and ICB ketorolac concentrations exceeded its IC(50) for COX-1 and COX-2 at peak and trough. Aqueous and ICB bromfenac levels exceeded its IC(50) for COX-2 at peak and trough, but not for COX-1 at trough aqueous levels and peak and trough ICB levels.

Conclusions: Both ketorolac 0.45% and bromfenac 0.09% effectively suppressed inflammation at peak. At trough, only ketorolac 0.45% effectively suppressed inflammation as measured by FITC-dextran leakage. The difference in inflammation suppression may be due to differences in tissue concentrations and/or greater COX-1 suppression by ketorolac 0.45%.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Aqueous Humor / drug effects
  • Aqueous Humor / metabolism
  • Benzophenones / pharmacokinetics
  • Benzophenones / pharmacology*
  • Bromobenzenes / pharmacokinetics
  • Bromobenzenes / pharmacology*
  • Dextrans / metabolism
  • Dinoprostone / analysis
  • Endophthalmitis / drug therapy*
  • Eye / metabolism*
  • Female
  • Fluorescein-5-isothiocyanate / analogs & derivatives
  • Fluorescein-5-isothiocyanate / metabolism
  • Ketorolac / pharmacokinetics
  • Ketorolac / pharmacology*
  • Lipopolysaccharides
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Rabbits

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzophenones
  • Bromobenzenes
  • Dextrans
  • Lipopolysaccharides
  • fluorescein isothiocyanate dextran
  • bromfenac
  • Prostaglandin-Endoperoxide Synthases
  • Fluorescein-5-isothiocyanate
  • Dinoprostone
  • Ketorolac