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R. S. Kadam, N. P. S. Cheruvu, U. B. Kompella; Influence of Lipophilcity and Melanin Binding on Delivery of Beta-blockers Across Bovine, Porcine, Rabbit, and Rat Eye Sclera-Choroid-RPE. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5951.
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Drug lipophilicity and affinity for macromolecules play an important role in determining the rate and extent of drug absorption across various tissues. This study determined the influence of solute lipophilicity and melanin binding on delivery of beta-blockers across bovine, porcine, rabbit, and rat sclera-choroid-RPE (SCRPE)
In vitro transport of a mixture of 8 beta-blockers across SCRPE was assessed using excised bovine, porcine, and rabbit (albino and pigmented) eyes. The donor cocktail included the following beta-blockers with varying log D7.4 (measured values at 37 oC are in parentheses): sotalol (-1.41), atenolol (-1.20), nadolol (-1.06), pindolol (-0.10), metoprolol (0.20), timolol (0.35), betaxolol (0.96), and propranolol (1.37). The donor concentration was either 100 µg/ml or 100 µM of each beta-blocker in assay buffer (pH 7.4). Receiver samples were collected over 6 hours. The in vitro melanin binding was determined using natural melanin (Sepia Officinalis). Further, tissue distribution of beta-blockers was assessed in euthanized Brown Norway rats after posterior subconjunctival injection. The samples were analyzed using an LC-MS/MS method.
The cumulative percent transport across SCRPE is significantly lower for lipophilic beta-blockers than hydrophilic beta-blockers in all four species. There is species difference in the extent of transport, with the rank orders for cumulative % transport being: albino rabbit> pigmented rabbit> porcine> bovine. Drug lipophilcity and melanin binding correlated inversely with the cumulative % transport across SCRPE. At the end of transport studies, the tissue accumulation of lipophilic beta-blockers was significantly higher in pigmented tissues compared with the albino tissues. The vitreal concentrations of beta-blockers in the ex vivo rat study correlated positively with in vitro transport across bovine SCRPE with R2 = 0.87
Despite the anticipated differences in the magnitude of transscleral drug delivery in various species, the rank order of SCRPE transport is generally similar across various species for a series of compounds, with lipophilic, melanin binding drugs exhibiting the least transscleral delivery. Cross-species correlations for transscleral delivery are feasible, as evidenced by the relationship between in vitro permeability in bovine tissues and ex vivo tissue delivery observed in the rat model.
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