Famciclovir is the
diacetyl 6-deoxy derivative of the active
antiviral penciclovir that is for use in the treatment of
infections caused by the herpes family of viruses. The major pathway of conversion is via di-deacetylation to
BRL 42359, followed by oxidation to
penciclovir. On oral dosing of
famciclovir to humans, only
penciclovir and
BRL 42359 can be detected consistently in the plasma; thus, attention was focused on the oxidation reaction. This 6-oxidation occurred rapidly in human liver cytosol, had no requirement for cofactors, and followed simple Michaelis-Menten kinetics with a KM of 115 microM +/- 23 (N = 3). Using inhibitors of
xanthine oxidase (
allopurinol) and
aldehyde oxidase (
menadione and
isovanillin), the relative roles of these
enzymes in this process were determined. At a concentration of
BRL 42359 that reflected plasma concentrations observed in humans (4 microM), both
menadione (IC50 7 microM) and
isovanillin (IC50 15 microM) caused extensive inhibition of the 6-oxidation reaction. In contrast,
allopurinol caused no significant inhibition, confirming earlier in vivo work. At higher substrate concentrations (50 and 200 microM), the results with these inhibitors were broadly similar. These results provide strong evidence that
aldehyde oxidase and not
xanthine oxidase is responsible for the 6-oxidation of
BRL 42359 to
penciclovir in human liver cytosol, and this is likely to reflect the in vivo situation.