Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium

Abstract

ABSTRACTObjective: To compare the cyclooxygenase (COX) activity and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) ketorolac tromethamine (ketorolac) and bromfenac sodium (bromfenac).Methods: Cyclooxygenase activity and selectivity was determined in vitro by measuring prostaglandin E2 (PGE2) production following incubation of varying concentrations of NSAID with human recombinant COX‐1 or COX‐2 and arachidonic acid. Anti-inflammatory effects were evaluated in a rabbit model in which an ocular inflammatory response was induced by intravenous injection of 10 µg/kg lipopolysaccharide (LPS). In study animals, one eye was treated with 50 µL (+/–) ketorolac 0.4% (Acular LS) or bromfenac 0.09% (Xibrom) and the other eye with 50 µL buffered saline. In control animals, both eyes were treated with vehicle. All animals were treated twice: 2 hours and 1 hour before LPS.‡ Acular LS is a trade name of Allergan Inc, Irvine, CA, USA§ Xibrom is a trade name of ISTA Pharmaceuticals, Irvine, CA, USAMain outcome measures: PGE2 production in vitro, measured by enzyme immunoassay; fluorescein isothiocyanate (FITC)-dextran leakage into the anterior chamber, measured by fluorophotometry; aqueous PGE2 levels in vivo, measured by ELISA immunoassay.Results: Ketorolac was six times more active against COX‐1 ( IC50 = 0.02 µM) than COX‐2 ( IC50 = 0.12 µM) while bromfenac was ≈ 32 times more active against COX‐2 ( IC50 = 0.0066 µM) than COX‐1 ( IC50 = 0.210 µM). In the animal model, both drugs resulted in nearly complete inhibition of FITC-dextran leakage and PGE2 production in the anterior chamber of treated eyes. There was also a 79% inhibition ( p < 0.001) of FITC-dextran leakage in the contralateral eyes of bromfenac-treated rabbits, and a 22.5% inhibition (not statistically significant) in the contralateral eyes of ketorolac-treated rabbits.Conclusions: Ketorolac is relatively COX‐1 selective while bromfenac is potently selective for COX‐2 over COX‐1. In the animal model, both ketorolac 0.4% and bromfenac 0.09% demonstrated maximal anti-inflammatory activity in treated eyes. Only bromfenac 0.09% had a significant effect on the contralateral eye, suggesting possible systemic absorption of this drug.