title: Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits.
  
  
  METHODS
  The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits.
  
  
  RESULTS
  The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs.
  
  
  CONCLUSIONS
  Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and nepafenac for retinochoroidal inflammatory diseases.
authors.affiliation: Research Laboratories for Drug Development, Senju Pharmaceutical Co., Ltd., Kobe, Japan; Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kida
authors.affiliation: Research Laboratories for Drug Development, Senju Pharmaceutical Co., Ltd., Kobe, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Kozai
authors.affiliation: Research Laboratories for Drug Development, Senju Pharmaceutical Co., Ltd., Kobe, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Research Laboratories for Drug Development, Senju Pharmaceutical Co., Ltd., Kobe, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Isaka
authors.affiliation: Research Laboratories for Drug Development, Senju Pharmaceutical Co., Ltd., Kobe, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tokushige
authors.affiliation: Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Sakamoto
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism; D001577:Benzophenones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001969:Bromobenzenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002829:Choroid / Q000187:drug effects / Q000378:metabolism; D002853:Chromatography, Liquid; D051545:Cyclooxygenase 1 / Q000737:chemistry; D051546:Cyclooxygenase 2 / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D010648:Phenylacetates / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D053719:Tandem Mass Spectrometry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001577:Benzophenones; D001969:Bromobenzenes; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; D004008:Diclofenac; C014285:amfenac; C053083:bromfenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human