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S.P. Ayalasomayajula, U.B. Kompella; Retinal Celecoxib Delivery Following Subconjunctival Administration is 39-Fold Higher Compared to Systemic Administration . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4444.
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Purpose: The aim of this study was to quantify the relative advantage of the subconjunctival route compared to a systemic route for retinal drug delivery. While the prior studies relied on single-point data presentations, this study obtained a complete pharmacokinetic analysis. This study assessed the ocular tissue availability of celecoxib, a selective COX-2 inhibitor, capable of inhibiting diabetes-induced retinal vascular endothelial growth factor (VEGF) expression and vascular leakage. Methods: The plasma and ocular tissue distribution of celecoxib was determined in male Sprague Dawley rats following subconjunctival and intraperitoneal administrations. For subconjunctival administration, the animals were anesthetized with single dose of sodium pentobarbital (40 mg/Kg) and celecoxib solution (1 mg/mL) was administered at a dose of 75 µg using a 27 G needle. For intraperitoneal administration, celecoxib was suspended in 0.5% carboxymethyl cellulose and injected at a dose of 3000 µg. Following treatments, the animals were sacrificed at the end of 0.5, 1, 2, 3, 4, 8, and 12 hours, the blood was collected, and the eyes were enucleated and frozen. The plasma and ocular tissues including sclera, retina, vitreous, and cornea were isolated and celecoxib levels were determined using an HPLC method. The tissue availability was measured as the area under the curve AUC0-contains. Results: The AUC0-contains of celecoxib was 28.2 ± 4.8, 16.82 ± 1.55, 37.09 ± 2.56, 32.57 ± 7.7, 16.77 ± 3.1, and 6002 ± 612.19 (units: ng.hr/ml in plasma and ng.hr/mg in other tissues) in sclera, retina, vitreous, cornea, and plasma, respectively, following intraperitoneal administration. The corresponding AUCs following subconjunctival administration were 16.38 ± 7.89, 21.29 ± 5.89, 22.7 ± 7.2, and 94.61 ± 24.49 in the retina, vitreous, cornea, and plasma, respectively. Thus, the dose-normalized relative availability of celecoxib was 39, 23, 28, and 0.6 in the retina, vitreous, cornea, and plasma respectively. Conclusions: The retinal delivery of celecoxib is substantially higher following subconjunctival administration compared to the intraperitoneal route. Systemic absorption of celecoxib is substantially lower following subconjunctival administration, suggesting that transscleral diffusion of celecoxib is responsible for the enhanced retinal delivery. Subconjunctival route is also more beneficial compared to the systemic route in delivering the drug to the vitreous and cornea.
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