In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver.
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.
Rashidi
M R
MR
Pharmaceutical Chemistry, School of Pharmacy, University of Bradford, UK.
Smith
J A
JA
Clarke
S E
SE
Beedham
C
C
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000212:Acyclovir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D042931:Aldehyde Oxidase; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077595:Famciclovir; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
C108016:6-deoxypenciclovir; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D015075:2-Aminopurine; D014969:Xanthine Oxidase; D000445:Aldehyde Oxidoreductases; D042931:Aldehyde Oxidase; D000077595:Famciclovir; D000212:Acyclovir