Metabolites of Isopropyl Unoprostone as Potential Ophthalmic Solutions to Reduce Intraocular Pressure in Pigmented Rabbits

Abstract

The intraocular metabolism of isopropyl unoprostone, a novel prostaglandin-related antiglaucoma compound, was investigated using pigmented rabbits to clarify which metabolites are involved in actions in the eye. Tritium-labeled isopropyl unoprostone eyedrops were administered. The cornea, aqueous humor, iris, ciliary body and retina were then collected at 5, 15 or 30 min or at 2, 6 or 12 h after instillation. Isopropyl unoprostone and its metabolites were fractionated using high-performance liquid chromatography, and the radioactivity of each fraction was measured. Unmetabolized isopropyl unoprostone was never detected in any sample at any time point. In the cornea, only the de-esterificated metabolite,Ml, and the further metabolized compound, M2, were detected; and the concentrations of these metabolites decreased with time. In the aqueous humor, Ml, M2 and another metabolite, M3, were detected, with peak concentrations of Ml at 30 min and M2 at 2 h. The iris and ciliary body showed a similar metabolism with peak concentrations of Ml and M2 at 30 min. In the aqueous humor, iris and ciliary body, M2 was the dominant metabolite from 30 min. In the retina, only total radioactivity was detected. These results indicate that the main metabolites involved in actions in the eye are Ml and M2.