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P. Challa, T. Inoue, V. Rao, J. J. Arnold; Evaluation of the Ocular Distribution and Effects on the Corneal Permeability Barrier of a Specific Rho-Associated Protein Kinase Inhibitor, Y-27632. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5165.
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The mechanism by which ROCK inhibitors induce intraocular pressure (IOP)-lowering is due to the ability of these drugs to provide alterations of actin microfilaments and decreased focal adhesion formation in TM cells leading to cellular rounding and widened intercellular spaces. These cellular effects might be expected to enhance the ocular penetration of other concomitantly administered ocular hypotensives. The purpose of this work was to assess the ocular distribution and subsequent effect of a ROCK specific inhibitor on the corneal permeability barrier.
Y-27632, a specific ROCK inhibitor, was formulated in eye-drops at a concentration of 10 mM and administered to male Dutch-belted (DB) rabbits. Animals were sacrificed at various times post eye-drop administration. Subsequently, ocular tissues were isolated and assayed for Y-27632 content via high pressure liquid chromatography (HPLC). In order to assess the potential effects of Y-27632 on the corneal permeability barrier, penetration of timolol maleate (5 mM) across porcine corneas isolated in side-by-side diffusion chambers was measured after 3 hours in the presence or absence of Y-27632 (0.1%).
At 0.5 and 8 hours post eye-drop administration to DB rabbits, the highest ocular tissue concentrations of Y-27632 were noted in the cornea (cornea: 2.5 ng/mg at 0.5 hours and 0.40 ng/mg at 8 hours, sclera-conjunctiva: 1.6 ng/mg at 0.5 hours and 0.07 ng/mg at 8 hours, iris-ciliary body: 0.89 ng/mg at 0.5 hours and 0.22 ng/mg at 8 hours, aqueous humor: 0.72 ng/ml at 0.5 hours and none detected at 8 hours, lens: none detected, vitreous humor: none detected, retina: none detected). No Y-27632 was detected in any ocular tissue at 24 hours after eye-drop administration. The penetration of timolol maleate across porcine corneas was assessed in the presence and absence of Y-27632 in side-by-side diffusion cells. The total amount of timolol maleate that penetrated after 3 hours of incubation was decreased, although not significantly, in the presence of Y-27632 (plus Y-27632: 1.7 ± 0.9 µg, minus Y-27632: 2.2 ± 0.9 µg).
Following eye-drop administration of Y-27632, peak and prolonged ocular tissue concentrations are achieved in the cornea. Despite these locally high concentrations, the corneal penetration of timolol appears to be diminished in the presence of Y-27632. Y-27632 does not enhance the corneal penetration of timolol.
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