title: In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac.
abstract: OBJECTIVE
  To evaluate the aqueous humor concentrations and cyclooxygenase (COX) inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac after topical ocular administration of Nevanac (nepafenac 0.1%), Acular LS (ketorolac 0.4%), or Xibrom (bromfenac 0.09%).
  
  
  METHODS
  Five private ophthalmology practices throughout the United States.
  
  
  METHODS
  Patients requiring cataract extraction were randomized to 1 of 3 treatment groups: Nevanac, Acular LS, or Xibrom. Patients were administered 1 drop of the test drug 30, 60, 120, 180, or 240 minutes before cataract surgery. At the time of paracentesis, an aqueous humor sample was collected and later analyzed for drug concentration. In addition, COX-1 (homeostatic) and COX-2 (inducible) inhibitory activities of nepafenac, amfenac, ketorolac, and bromfenac were determined via the in vitro measurement of prostaglandin E(2) (PGE(2)) inhibition.
  
  
  RESULTS
  Seventy-five patients participated in the study. The prodrug nepafenac had the shortest time to peak concentration and the greatest peak aqueous humor concentration (C(max)). The C(max) of nepafenac was significantly higher than that of the other drugs (P<.05), including the higher-concentration ketorolac (0.4%). The area under the curve (AUC) of nepafenac was significantly higher (P<.05) than the AUCs of amfenac, ketorolac, and bromfenac. The combined AUCs of nepafenac and amfenac were the highest of all drugs tested (P<.05). Ketorolac showed the most potent COX-1 inhibition, whereas amfenac was the most potent COX-2 inhibitor. The PGE(2) aqueous humor levels of each study medication were highly variable; as a result, meaningful interpretation of the data was not possible.
  
  
  CONCLUSIONS
  Nepafenac showed significantly greater ocular bioavailability and amfenac demonstrated greater potency at COX-2 inhibition than ketorolac or bromfenac.
authors.affiliation: Keystone Research, Department of Ophthalmology, 1020 West 34th Street, Austin, Texas 78705, USA. twalters@austin.rr.com
authors.forename: Tom
authors.initials: T
authors.lastname: Walters
authors.forename: Michael
authors.initials: M
authors.lastname: Raizman
authors.forename: Paul
authors.initials: P
authors.lastname: Ernest
authors.forename: Johnny
authors.initials: J
authors.lastname: Gayton
authors.forename: Robert
authors.initials: R
authors.lastname: Lehmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism*; D019540:Area Under Curve; D044482:Benzeneacetamides / Q000493:pharmacokinetics / Q000494:pharmacology; D001577:Benzophenones / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D001969:Bromobenzenes / Q000493:pharmacokinetics / Q000494:pharmacology; D002387:Cataract Extraction; D002851:Chromatography, High Pressure Liquid; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D020910:Ketorolac / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010648:Phenylacetates / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D044482:Benzeneacetamides; D001577:Benzophenones; D001969:Bromobenzenes; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; C414203:nepafenac; C014285:amfenac; C053083:bromfenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D020910:Ketorolac