Vitreal Pharmacokinetics of Dipeptide Monoester Prodrugs of Ganciclovir

Abstract

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. 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. 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. 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.