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S.K. Singh, M. Shawer, P.K. Andrus, T.J. Raub, J.J. Vrbanac; Ocular Delivery Screening Scheme for Systemically Administered Ophthalmic Drugs . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4426.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Systemic delivery of ophthalmic drug is an attractive approach for targeting ocular tissues that may not be accessed by topical administration especially for diseases associated with the posterior segment of the eye. Due to the generation of a high number of compounds in the pharmaceutical industry that may have pharmacological efficacy, a quick and easy method needs to be established for screening lead compounds with a suitable ocular/plasma distribution. In this study we established the ocular distribution and physicochemical characteristics of four different compounds, thalidomide, memantine, brimonidine, and aminoguanidine. Methods: The methodology was based on a combination of 3 sets of experiments: MDCK cellular permeability (and P-glycoprotein effect), protein binding, and in vivo (mouse, n= - 3 per time point) ocular/plasma distribution. LC/MS/MS was used to quantify the substances. Plasma volume in the eye of the mouse was established to be 92 µL/g by using [14C]inulin. Statistical significance of means was assessed by ANOVA. Results: Plasma protein binding of memantine, aminoguanidine and brimonidine was low at < 15%.Thalidomide and memantine were not substrates of P-gp. Ocular/plasma distribution (%) at 5 min was 54±19, 544±166, 26±10, and 126±23 for thalidomide, memantine, aminoguanidine, and brimonidine respectively. The ocular/plasma distribution (%) at 60 min was 154±25, 479±90, 168±49, and 202±21 for thalidomide, memantine, aminoguanidine, and brimonidine respectively. Elimination from the eye was similar to or slightly slower than the plasma. Memantine elicited significantly higher ocular/plasma distribution than the rest of the compounds at both 5 and 60 min (P<0.05, ANOVA). Conclusions: The results of this pilot study suggests a relationship between compound physicochemical properties and ocular distribution in vivo as related to passive diffusion. This screening method proved to be time and resource efficient for identifying lead compounds based on limited in vitro and in vivo experiments. Acknowledgements: BS Lutzke, RJ LeMay, and GA Sawada
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