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Mark S. Hansen, John J. Arnold, Gregory S. Gorman, Vasanth Rao, Pratap Challa; The Effect of a Rho-Associated Kinase (ROCK) Inhibitor on the Ocular Distribution of Timolol Maleate in New Zealand White Rabbits. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3229.
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To assess the in vivo effect of Y-27632, a ROCK specific inhibitor, on the ocular distribution of timolol maleate. ROCK inhibitors have been previously shown to increase the intercellular space between cells. The effect this might have on the in vivo penetration of another ocular hypotensive drug is presently unknown.
In order to assess the potential effects of Y-27632 on the ocular distribution of timolol maleate both in vitro and in vivo experiments were carried out. The cumulative penetration of timolol maleate (0.5%) across porcine corneas isolated in side-by-side diffusion chambers was measured after 12 hours in the absence or presence of Y-27632 (1%). The in vivo distribution of timolol was measured after topical administration of formulations of timolol (0.5%) with and without Y-27632 (1%) in retina, lens, cornea, conjunctiva/sclera, vitreous and aqueous humor using LC-tandem mass spectrometry. The concentration of both Y-27632 and timolol maleate was based on mix reaction monitoring (MRM) using internal standard quantitation.
The corneal penetration of timolol maleate across porcine corneas was assessed in the presence and absence of Y-27632 in side-by-side diffusion cells. Interestingly, the total amount of timolol maleate that penetrated after 12 hours of incubation was actually decreased, although not significantly, in the presence of Y-27632 (plus Y-27632: 99 ± 36 µg, minus Y-27632: 110 ± 31 µg). The bioistribution of timolol maleate in each of the eye tissues will be compared to the in vitro results in terms of mass of active compound per mass of tissue.
The ROCK specific inhibitor, Y-27632, appears to have little effect on corneal penetration of timolol maleate in the in vitro experiments. These results suggest that this new class of ocular hypotensives can be administered concurrently with established agents.
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