IN-VITRO OXIDATION OF FAMCICLOVIR AND 6-DEOXYPENCICLOVIR BY ALDEHYDE OXIDASE FROM HUMAN, GUINEA-PIG, RABBIT, AND RAT-LIVER

Famciclovir, a 9-substituted guanine derivative, is a new antiviral ag ent which undergoes rapid hydrolysis and oxidation in man to yield the active antiherpes agent, penciclovir. Studies with human liver cytoso l have indicated that the oxidation of the penultimate metabolite, 6-d eoxypenciclovir, to penciclovir is catalyzed by the molybdenum hydroxy lase, aldehyde oxidase. In the present study the oxidation of famciclo vir and 6-deoxypenciclovir with partially purified molybdenum hydroxyl ases from human, guinea pig, rabbit, and rat livers and bovine milk xa nthine oxidase has been investigated. Famciclovir and 6-deoxypenciclov ir were oxidized predominantly to 6-oxo-famciclovir and penciclovir, r espectively, by human, guinea pig, and rat liver aldehyde oxidase. Sma ll amounts of 8-oxo and 6,8-dioxo-metabolites were also formed from ea ch substrate. Famciclovir and 6-deoxypenciclovir were good substrates for rabbit liver aldehyde oxidase but, in each case, two major metabol ites were formed. 6-Deoxypenciclovir was converted to penciclovir and 8-oxo-6-deoxypenciclovir in approximately equal quantities; famciclovi r was oxidized to 6-oxo-famciclovir and a second metabolite which, on the basis of chromatographic and UV spectral data, was thought to be 8 -oxo-famciclovir. Two groups of Sprague Dawley rats were identified; t hose containing hepatic aldehyde oxidase and xanthine oxidase and thos e with only xanthine oxidase. These have been designated AO-active and AO-inactive rats, respectively. Famciclovir was not oxidized by enzym e from AO-inactive rats or bovine milk xanthine oxidase although 6-deo xypenciclovir was slowly converted to penciclovir by rat liver or milk xanthine oxidase. Inhibitor studies showed in human, guinea pig, and rabbit liver that xanthine oxidase did not contribute to the oxidation of famciclovir and 6-deoxypenciclovir; thus it is proposed that drug activation in vivo would be catalyzed solely by aldehyde oxidase.