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D. Kwatra, S. Katragadda, S. Gunda, S. Hariharan, A. K. Mitra; Anterior Chamber Ocular Pharmacokinetics of Acyclovir Amino Acid Ester Prodrugs: Evaluation of Their Utility in Treating Ocular HSV Infections. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4268.
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In vivo corneal absorption of the amino acid prodrugs of acyclovir (ACV) was evaluated using a topical well model and microdialysis in rabbits.
A corneal well was placed on the cornea of the anesthetized New Zealand White rabbits with implanted linear probes into the aqueous humor. Two hundred microlitres of a 0.25% solution of L-Alanine-ACV (AACV), L-Serine-ACV (SACV), L-Isoleucine-ACV (IACV), γ-Glutamate-GCV (EACV) and L-Valine-ACV (VACV) was placed in the corneal well and was allowed to diffuse for a period of 2 hours. Samples were collected every twenty minutes throughout the infusion and post infusion phases and were analyzed by HPLC. Degradation rates of these prodrugs were evaluated in various ocular tissues. Dose dependent toxicity of these prodrugs was also tested in rabbit primary corneal epithelial cell culture (rPCEC).
In terms of prodrugs stability, SACV is most stable in aqueous humor compared to all other prodrugs. EACV enzymatic degradation is less compared to all other prodrugs. Cellular toxicity of all the ACV prodrugs was significantly less compared to TFT. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. SACV exhibited the comparable in vivo corneal absorption rate constant (ka) as VACV but all the prodrugs showed similar terminal elimination rate (z). The time of maximum absorption (Tmax) of ACV after administration of VACV and the amino acid ester prodrugs did not vary significantly (p<0.05). Dose normalized AUC value for cumulative amounts of ACV absorbed for SACV was also comparable to VACV.
Amino acid ester prodrugs of ACV were absorbed through the cornea at similar rates but varying extents. The amino acid ester prodrug, SACV owing to its enhanced absorption of ACV seems to be a promising candidate for the treatment of ocular HSV infections.
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