Corneal absorption and anterior chamber pharmacokinetics-of dipeptide monoester prodrugs of ganciclovir (GCV):: In vivo comparative evaluation of these Prodrugs with Val-GCV and GCV in rabbits

Aim: The overall aim of this study was to evaluate the corneal absorption of dipeptide monoester prodrugs of ganciclovir (GCV) and compare these results with L-valine-GCV and GCV. Another aim was to evaluate the pharmacokinetics of these prodrugs in aqueous humor. Methods: A well was placed on the cornea of anesthetized New Zealand albino rabbits with linear probes implanted in the aqueous humor. Two hundred microlitres (200 mu L) of a 0.43% W/V (saturation concentration) solution of GCV and equimolar concentrations of its prodrugs, VGCV, glycine-valine-GCV (GVGCV), valine-valine-GCV (VVGCV), and tyrosine-valine-GCV (YVGCV), were placed in the corneal well and were allowed to diffuse for a period of 2 h. Subsequently, the drug solution was aspirated and the well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by high-performance liquid chromatography to determine the aqueous humor concentrations. Results: Area under the concentration time profile (AUC)(infinity) and maximum concentration (C-max) of YVGCV were found to be higher than other prodrugs. AUC of total GCV obtained from YVGCV administration was found to be twelvefold more than AUC of GCV and 6.2-fold more than AUC obtained with total GCV from VGCV administration. VVGCV also exhibited 3.2 times higher AUC relative to VGCV. Also, AUC and C-max of regenerated GCV from YVGCV was 8.6 and 4.9 times more than GCV, respectively. VVGCV did not produce higher concentrations of GCV. Elimination half-life of regenerated GCV from YVGCV administration was observed to be 157 min. Conclusions: YVGCV and VVGCV exhibited superior corneal absorption and bioavailability, in comparison with GVGCV, VGCV, and GCV. Such facilitated absorption of prodrugs may be a result of a combination of transcellular passive diffusion and peptide transporter (PEPT1)-mediated transport across the corneal epithelium.