Corneal permeation of ganciclovir: mechanism of ganciclovir permeation enhancement by acyl ester prodrug design.J Ocul Pharmacol Ther. 2002 Dec; 18(6):535-48.JO
Ganciclovir (GCV), a promising antiviral compound, has poor ocular bioavailability as a result of its relatively low partition coefficient. In this study, lipophilic ester prodrugs of GCV were synthesized in an effort to improve its uptake into ocular tissues. In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic mono-acyl ester prodrugs of GCV to determine the effect of lipophilicity and corneal hydrolysis rate on transcorneal diffusion. The GCV prodrugs showed a progressive decrease in solubility and a corresponding increase in Log P values as the chain length was ascended. Permeation studies using freshly isolated rabbit corneas showed that all prodrugs permeated as intact prodrug as well as hydrolyzed GCV. Corneal permeability coefficients increased with increasing lipophilicity for mono-ester prodrugs having more than three carbon atoms in the side chain. The permeability of GCV increased about 6-fold in ascending from the parent drug-ganciclovir (3.82 +/- 0.19 x 10(-6) cm sec(-1)) to its valerate ester prodrug (23.70 +/- 1.36 x 10(-6) cm sec(-1)). Among the prodrugs studied, the valerate ester showed the highest permeability and holds the most potential for development. Overall prodrug permeability correlated linearly with increased susceptibility of the GCV esters to undergo hydrolysis in the cornea. The present work indicates that the ideal prodrug is one that not only possesses enhanced partitioning characteristics, but also high enzyme susceptibility. Concentration of active GCV penetrating the corneal epithelium was substantially increased through the bio-reversible ester prodrug strategy.