Abstract

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.