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 µL) 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
(Cmax) 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 Cmax 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.
