title: Ocular penetration and anti-inflammatory activity of ketorolac 0.45% and bromfenac 0.09% against lipopolysaccharide-induced inflammation.
abstract: OBJECTIVE
  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%.
authors.affiliation: Raven Biosolutions LLC, San Carlos, CA 94070, USA. david_waterbury@yahoo.com
authors.forename: L David
authors.initials: LD
authors.lastname: Waterbury
authors.forename: Danielle
authors.initials: D
authors.lastname: Galindo
authors.forename: Linda
authors.initials: L
authors.lastname: Villanueva
authors.forename: Cathy
authors.initials: C
authors.lastname: Nguyen
authors.forename: Milan
authors.initials: M
authors.lastname: Patel
authors.forename: Lisa
authors.initials: L
authors.lastname: Borbridge
authors.forename: Mayssa
authors.initials: M
authors.lastname: Attar
authors.forename: Rhett M
authors.initials: RM
authors.lastname: Schiffman
authors.forename: David A
authors.initials: DA
authors.lastname: Hollander
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism; D001577:Benzophenones / Q000493:pharmacokinetics / Q000494:pharmacology*; D001969:Bromobenzenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D003911:Dextrans / Q000378:metabolism; D015232:Dinoprostone / Q000032:analysis; D009877:Endophthalmitis / Q000188:drug therapy*; D005123:Eye / Q000378:metabolism*; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D020910:Ketorolac / Q000493:pharmacokinetics / Q000494:pharmacology*; D008070:Lipopolysaccharides; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001577:Benzophenones; D001969:Bromobenzenes; D003911:Dextrans; D008070:Lipopolysaccharides; C015219:fluorescein isothiocyanate dextran; C053083:bromfenac; D011451:Prostaglandin-Endoperoxide Synthases; D016650:Fluorescein-5-isothiocyanate; D015232:Dinoprostone; D020910:Ketorolac