ROLE OF ALDEHYDE OXIDASE IN THE IN-VITRO CONVERSION OF FAMCICLOVIR TOPENCICLOVIR IN HUMAN LIVER

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 d i-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 focuse d on the oxidation reaction. This 6-oxidation occurred rapidly in huma n liver cytosol, had no requirement for cofactors, and followed simple Michaelis-Menten kinetics with a K-M of 115 mu M +/- 23 (N = 3). Usin g inhibitors of xanthine oxidase (allopurinol) and aldehyde oxidase (m enadione and isovanillin), the relative roles of these enzymes in this process were determined. At a concentration of BRL 42359 that reflect ed plasma concentrations observed in humans (4 mu M), both menadione ( IC50 7 mu M) and isovanillin (IC50 15 mu M) caused extensive inhibitio n of the 6-oxidation reaction. In contrast, allopurinol caused no sign ificant inhibition, confirming earlier in vivo work, At higher substra te concentrations (50 and 200 mu M), the results with these inhibitors were broadly similar. These results provide strong evidence that alde hyde oxidase and not xanthine oxidase is responsible for the 6-oxidati on of BRL 42359 to penciclovir in human liver cytosol, and this is lik ely to reflect the in vivo situation.