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

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....