Mr. Rashidi et al., IN-VITRO OXIDATION OF FAMCICLOVIR AND 6-DEOXYPENCICLOVIR BY ALDEHYDE OXIDASE FROM HUMAN, GUINEA-PIG, RABBIT, AND RAT-LIVER, Drug metabolism and disposition, 25(7), 1997, pp. 805-813
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.