Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments

David F. Woodward, Stacey L. Wenthur, Tara L. Rudebush, Shan Fan, Carol B Toris

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Purpose: 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. Methods: 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. Results: 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 EP1 antagonist SC-51322 failed to penetrate sufficiently to be bioavailable in the aqueous humor and ciliary body/iris. This obliged testing an alternative EP1 antagonist, namely ONO-8713, to reliably conclude that an EP1 antagonist does not alter IOP. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)606-622
Number of pages17
JournalJournal of Ocular Pharmacology and Therapeutics
Volume32
Issue number9
DOIs
StatePublished - Nov 1 2016

Fingerprint

Intraocular Pressure
Prostaglandins
Biological Availability
Rabbits
Haplorhini
Thromboxane Receptors
Ocular Hypertension
Ciliary Body
Tissue Extracts
Aqueous Humor
Iris
Solubility
Lasers
Pharmacokinetics

Keywords

  • Prostanoid antagonist
  • aqueous humor
  • bioavailability
  • ciliary body/iris
  • cornea
  • intraocular pressure

ASJC Scopus subject areas

  • Ophthalmology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Prostanoid Receptor Antagonist Effects on Intraocular Pressure, Supported by Ocular Biodisposition Experiments. / Woodward, David F.; Wenthur, Stacey L.; Rudebush, Tara L.; Fan, Shan; Toris, Carol B.

In: Journal of Ocular Pharmacology and Therapeutics, Vol. 32, No. 9, 01.11.2016, p. 606-622.

Research output: Contribution to journalArticle

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