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

ABSTRACT

Objective: 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.

Main 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.