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Pharmaceutical Chemistry, School of Pharmacy, University of
Bradford (M.R.R., J.A.S., C.B.), and
SmithKline Beecham (S.E.C)
Famciclovir, a 9-substituted guanine derivative, is a new antiviral
agent which undergoes rapid hydrolysis and oxidation in man to yield
the active antiherpes agent, penciclovir. Studies with human liver
cytosol have indicated that the oxidation of the penultimate
metabolite, 6-deoxypenciclovir, to penciclovir is catalyzed by the
molybdenum hydroxylase, aldehyde oxidase. In the present study the
oxidation of famciclovir and 6-deoxypenciclovir with partially purified
molybdenum hydroxylases from human, guinea pig, rabbit, and rat livers
and bovine milk xanthine oxidase has been investigated. Famciclovir and
6-deoxypenciclovir were oxidized predominantly to 6-oxo-famciclovir and
penciclovir, respectively, by human, guinea pig, and rat liver aldehyde
oxidase. Small amounts of 8-oxo and 6,8-dioxo-metabolites were also
formed from each substrate. Famciclovir and 6-deoxypenciclovir were
good substrates for rabbit liver aldehyde oxidase but, in each case,
two major metabolites were formed. 6-Deoxypenciclovir was converted to
penciclovir and 8-oxo-6-deoxypenciclovir in approximately equal
quantities; famciclovir 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; those containing hepatic aldehyde oxidase and xanthine
oxidase and those with only xanthine oxidase. These have been
designated AO-active and AO-inactive rats, respectively. Famciclovir
was not oxidized by enzyme from AO-inactive rats or bovine milk
xanthine oxidase although 6-deoxypenciclovir 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.
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