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Rajendra S. Kadam, Henry F. Edelhauser, Uday B. Kompella; Transport Of Beta-blockers Across Human Sclera-choroid-rpe And Correlation With Bovine, Porcine, Rabbit, And Rat Models. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2054.
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In vitro permeability across biological membranes may help select drug candidates for further development.Due to the limited availability of human tissues, permeability screening is routinely performed in various preclinical models. This study determined the in vitro transport of a series of beta-blockers across human sclera-choroid-RPE (SCRPE) and developed cross species correlations with various preclinical models.
In vitro transport of a mixture of 8 beta-blockers across human SCRPE was assessed using modified Ussing chambers. The donor solution (pH 7.4) included the following beta-blockers, each at 100 µg/ml,: sotalol, atenolol, nadolol, pindolol, metoprolol, timolol, betaxolol, and propranolol. Permeability studies were conducted at 37 oC over 6 hours. The samples were analyzed using an LC-MS/MS method. The ex vivo delivery to the vitreous was assessed in euthanized Brown Norway rats after posterior subconjunctival injection. In vitro transport data for bovine, porcine and rabbit SCRPE were measured in our previous studies. Transport across SCRPE was normalized with SCRPE thickness and melanin content in choroid-RPE to explain species differences. The cross species correlation was performed using Sperman’s Rho rank order correlation.
Solute lipophilicity correlated inversely with cumulative %transport across human SCRPE (R2 = 0.89). Beta-blocker transport exhibited species differences, with the rank order for cumulative % transport being: albino rabbit > pigmented rabbit > human > porcine > bovine. Correction of cumulative % transport to SCRPE thickness and melanin content significantly reduced species differences. The cross species comparison of human data with all 4 preclinical species showed very good Spearman's Rho correlation with R2 ≥ 0.91. The vitreal concentrations in the ex vivo rat study correlated positively with in vitro transport across human SCRPE with R2 = 0.71.
Although different in magnitude between species, sclera-choroid-RPE transport can be correlated between species. Differences in tissue thickness and melanin content largely account for the species differences in SCRPE transport. Cross-species correlations for transscleral delivery are feasible, as evidenced by the Spearman's Rho correlation and the correlation between in vitro permeability in human tissues and ex vivo transscleral delivery to the vitreous in the rat model
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