title: Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments.
abstract: Since all prostanoid receptors affect intraocular pressure (IOP) and endogenous prostanoids are found in ocular tissues, the pressor effects of prostanoid antagonists were comprehensively evaluated. The absence of effects of most of these antagonists was not entirely anticipated. To ensure no false-negative results, ocular biodisposition studies were conducted.
  
  
  
  Monkeys with laser-induced ocular hypertension were used to study antagonist effects on IOP. Ocular biodisposition of each antagonist was assessed in rabbits, with LC/MS/MS analyses of tissue extracts and blood.
  
  
  
  EP1, EP2, EP3, EP4, FP, IP, and TP prostanoid receptor antagonists did not affect IOP, even at a high 1% dose. These studies were followed by ocular biodisposition studies. Striking differences in ocular tissue bioavailability were observed, which were independent of solubility. Only the EP1antagonist SC-51322 failed to penetrate sufficiently to be bioavailable in the aqueous humor and ciliary body/iris. This obliged testing an alternative EP1antagonist, namely ONO-8713, to reliably conclude that an EP1antagonist does not alter IOP.
  
  
  
  These antagonist studies provided no evidence for individual endogenous prostanoids exerting a meaningful role in regulating IOP. They do reaffirm the critical importance of studying ocular bioavailability for confirming negative data. Large differences among the antagonists in anterior segment and even ocular surface tissue biodisposition were observed in rabbits. It appears from these monkey studies, supported by rabbit ocular bioavailability data, that an absence of drug effect in the eye cannot be adequately substantiated without determination of ocular pharmacokinetics.
authors.affiliation: 1 Department of Biological Sciences, Allergan, Inc. , Irvine, California.
authors.forename: David F
authors.initials: DF
authors.lastname: Woodward
authors.affiliation: 2 Department of Ophthalmology and Visual Science, School of Medicine, University of Nebraska Medical Center , Omaha, Nebraska.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Wenthur
authors.affiliation: 2 Department of Ophthalmology and Visual Science, School of Medicine, University of Nebraska Medical Center , Omaha, Nebraska.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Rudebush
authors.affiliation: 2 Department of Ophthalmology and Visual Science, School of Medicine, University of Nebraska Medical Center , Omaha, Nebraska.
authors.forename: Shan
authors.initials: S
authors.lastname: Fan
authors.affiliation: 2 Department of Ophthalmology and Visual Science, School of Medicine, University of Nebraska Medical Center , Omaha, Nebraska.|3 Department of Ophthalmology and Visual Science, School of Medicine, Case Western Reserve University , Cleveland, Ohio.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Toris
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005123:Eye / Q000378:metabolism*; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects*; D007834:Lasers; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012995:Solubility; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C522100:AS604872; D000178:Acrylamides; D001384:Azetidines; D001713:Biphenyl Compounds; C508710:L-826266; D009281:Naphthalenes; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C570688:1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid
keywords: aqueous humor; bioavailability; ciliary body/iris; cornea; intraocular pressure; prostanoid antagonist