Purpose: The aim of this study was to determine vitreal pharmacokinetics of a series of
dipeptide monoester ganciclovir (GCV) prodrugs and to study their interaction with the retinal
peptide transporter.
Methods: New Zealand albino male rabbits were selected as the animal model. Ocular microdialysis technique was employed to delineate the pharmacokinetics of GCV, L-valine-GCV
and dipeptide monoester GCV prodrugs (L-valine-L-valine, L-tyrosine-L-valine, and L-glycine-
L-valine) following intravitreal administration.
Results: Val-GCV and Val-Val-GCV inhibited retinal uptake of [3H]Gly-Sar by 43% and
37%, respectively, suggesting that these prodrugs may be substrates of the retinal peptide
transport system. Val-GCV and Gly-Val-GCV were observed to be the most stable GCV prodrugs
in vitreous humor. All GCV prodrugs were rapidly converted to GCV in retinal homogenates.
Vitreal pharmacokinetic studies suggest that Val-GCV and Val-Val-GCV are
rapidly eliminated from the vitreous chamber, compared to GCV, whereas Gly-Val-GCV is
eliminated at a much slower rate. Retinal GCV concentrations generated from all three prodrugs,
at the end of 5 h, were almost equivalent and were almost twice that following intravitreal
administration of GCV. Gly-Pro, however, did not demonstrate any effect on retinal
uptake of Val-GCV or Gly-Val-GCV.
Conclusions: Considering retinal GCV concentrations generated and vitreal pharmacokinetic
profiles, Gly-Val-GCV appears to be a lead candidate for further in vivo evaluation
against human cytomegalovirus (HCMV) retinitis.
