EFFECT OF ACYLATION ON THE OCULAR DISPOSITION OF ACYCLOVIR .2. CORNEAL PERMEABILITY AND ANTI-HSV-1 ACTIVITY OF 2'-ESTERS IN RABBIT EPITHELIAL KERATITIS

In vitro permeability studies were conducted on isolated rabbit cornea l membranes using aliphatic acyl esters of acyclovir to determine the effect of lipophilicity on the transcorneal diffusion. Corneal membran e permeability coefficients increased with increasing lipophilicity of the straight chain aliphatic esters. The branch chain ester, acyclovi r isobutyrate, displayed an anomalously low corneal permeability when compared to acyclovir esters having similar molecular size and 1-octan ol/water partition coefficient. In vivo corneal penetration studies we re conducted on unanesthetized rabbits. The aqueous humor concentratio ns of acyclovir and the ester prodrugs were measured at twenty five mi nutes after the topical instillation of an aqueous solution of the app ropriate 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 increasi ng productive corneal absorption than the precorneal loss pathways. Th e effectiveness of acyclovir butyrate as a treatment for primary herpe tic 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.