Ocular absorption, distribution, and systemic absorption of a novel antiglaucoma medication, prostaglandin derivative, in male white rabbits

A prostaglandin derivative, (5Z,9α,11α,13E)-9,11-dihydroxyprosta-5,13- dienoic acid sodium salt (S-1033), that lowers intraocular pressure with little adverse effect, may have clinical value in the treatment of glaucoma. After [¹⁴C]S-1033 (0.2% solution) was instilled into the eye of a white rabbit, radioactivity and S-1033 appeared in systemic plasma so rapidly (t(max), 5 min) and S-1033 was eliminated very rapidly with half-lives of 2.8 and 11.0 min at α- and β-phases, respectively. The metabolite, M-1, [1R- [1α,2β(1E),3α,5α]]-3,5-dihydroxy-2-(1-octenyl)-cyclopentanepropanoic acid (tetranor-S-1033), appeared in plasma very rapidly (t(max), 5 min), suggesting that a fast metabolism was a major factor in the rapid elimination of S-1033 from plasma. The values for the ratios of the area under the curve of ocular instillation to intravenous administration for radioactivity and S- 1033 were 1.01 and 0.52, respectively, indicating that more than half of the S-1033 instilled was transported into the systemic circulation. To clarify the contributing pathway of the massive and rapid systemic absorption of S- 1033 after topical dosing, plasma levels of S-1033 were investigated after instillation to rabbits in which the nasolacrimal ducts were occluded. Plasma concentrations of S-1033 were slightly higher than those in intact rabbits, suggesting that conjunctiva would be as important as nasal mucosae for the systemic absorption under the physiological condition. As for the intraocular distribution, the highest levels of radioactivity were found in the cornea, conjunctiva, and anterior sclera. The uvea (iris and ciliary body), the probable target of S-1033, and the aqueous humor also showed high levels of radioactivity. The distribution to the uvea, as shown by the area under the curve value, was largest after that of the cornea among ocular tissues, probably via the corneal route. S-1033 concentrations in aqueous humor 1 hr after dosing accounted for >72% of the radioactivity, and tetranor-S-1033 accounted for almost all of the remainder. The chemical structure of M-1 was determined by comparison of the mass spectra, retention times on gas chromatograms, and high-performance liquid chromatograms, and R(F) values on thin layer chromatographs with those of the synthesized compound.