Effect of Acylation on the Ocular Disposition of Acyclovir II: Corneal Permeability and Anti-HSV 1 Activity of 2′-Esters in Rabbit Epithelial Keratitis

ABSTRACT

In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic acyl esters of acyclovir to determine the effect of lipophilicity on the transcorneal diffusion. Corneal membrane permeability coefficients increased with increasing lipophilicity of the straight chain aliphatic esters. The branch chain ester, acyclovir isobutyrate, displayed an anomalously low corneal permeability when compared to acyclovir esters having similar molecular size and 1-octanol/water partition coefficient. In vivo corneal penetration studies were conducted on unanesthetized rabbits. The aqueous humor concentrations of acyclovir and the ester prodrugs were measured at twenty five minutes after the topical instillation of an aqueous solution of the appropriate compound. The concentration of acyclovir in the aqueous humor increased with increasing 1-octanol/ water partition coefficient. The lipophilic modification was shown to have a greater effect on increasing productive corneal absorption than the precorneal loss pathways. The effectiveness of acyclovir butyrate as a treatment for primary herpetic keratitis was evaluated in the McKrae strain infected rabbit model. The compound did not lose activity due to the esterification of the 2′ hydroxyl group.