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S. Katragadda, B.S. Anand, A.K. Mitra; MechanismofCornealPermeationofAminoAcidEsterProdrugsofAcyclovir . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5048.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The aim of this study was to explore the feasibility of utilizing amino acid transporters on the rabbit cornea for improved bioavailability of the antiviral agent, Acyclovir (ACV). Methods:The chemical hydrolysis, enzymatic hydrolysis in various ocular tissues and transport characteristics of water–soluble amino acid prodrugs of ACV, ã–Glutamate–ACV (EACV) and L–Tyrosine–ACV (YACV) were studied across freshly excised rabbit cornea. Results:EACV inhibited the uptake of [3H] L–Arg across rPCEC and also exhibited an appreciable half–life in cornea in comparison to YACV. The transport of EACV was found to be concentration, energy dependent and sodium dependent and independent of pH and also inhibited in presence of neutral amino acids, cationic amino acids, ornithine and BCH (specific inhibitor for L–type system). On the other hand YACV was not recognized by the amino acid transporters as it failed to inhibit the uptake of [3H] Arg and also its transport across cornea was not inhibited by arginine. YACV and EACV exhibited excellent antiviral activity against HSV–1 & 2 and VZV in comparison to ACV. Conclusion:Analyses of the pattern of inhibition of transport of EACV suggests the involvement of a single transport system namely B0,+. Design of amino acid prodrugs seems to be an attractive strategy to enhance the solubility of the otherwise poorly aqueous soluble compounds and also to afford a targeted and possibly enhanced delivery of the active drug.
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