Targeting of Acyclovir to the Brain via a Lipophilic and Water Soluble Prodrug

Abstract

[9-(2-hydroxyethoxymethyl)guanine] or acyclovir (ACV) is a nucleoside analog that has high antiviral activity for herpes simplex virus (HSV) (Laskin, 1984). While oral dosage forms have been successful in ceasing viral shedding in genital infections, oral forms of ACV do not reach adequate levels to inhibit viral replication in the CNS (Corey, 1985). This is due to 1) low bioavailability of ACV to the plasma following oral administration and 2) restriction of transport of the relatively polar ACV to the brain by the blood brain barrier (BBB). We synthesized ester prodrugs of ACV to create a prodrug of ACV that could cross the BBB by passive diffusion thereby increasing concentration of ACV in the brain. Lipophilicity studies indicate that esters with chains of C5 and longer should be able to diffuse passively across the BBB. Ester prodrugs must be reconverted back to the parent form to be active. Use of the inhibitor PMSF showed significant inhibition on the degradation of the esters implying that esterase activity is present, reconverting the prodrug back to the active form. Esterase activity was found to be dependent upon the structure of the ester substituent. Lipophilicity increases were accompanied with decreases in aqueous solubility which is thought to restrict bioavailability of an oral dosage (Krenitsky,1986). A scheme to enhance solubility by removal of an exocyclic amino group was not found to produce increases in solubility adequate for an oral form.