Deglycosylation of antiherpesviral 5-substituted arabinosyluracil derivatives by rat liver extract and enterobacteria cells.
A number of antiherpesviral 5-substituted derivatives of 1-beta-D-arabinofuranosyluracil (araU) were significantly resistant to phosphorolysis by rat liver extract (S-9), but were gradually deglycosylated in a 2% enterobacteria cell suspension. The relative order of the resistance conferred by the different C-5 substituents was: 5-propynyl > 5-(E)-2-bromovinyl > 5-(E)-2-chlorovinyl > 5-methyl > 5-iodo. The 2'-fluoro derivatives of araU were completely resistant to phosphorolysis by both liver extract and enterobacteria, whereas the corresponding ribofuranosyl and 2'-deoxyribofuranosyl nucleosides were easily phosphorolysed by S-9, and were immediately cleaved in a 1% enterobacteria cell suspension. These findings suggest that antiherpesviral 5-substituted araU analogues can be relatively stable in vivo, when injected intravenously, and that degradation of 1-beta-D-arabinofuranosyl-5-(E-2-bromovinyl)uracil (sorivudine) following oral administration is due primarily to the action of enterobacteria.
Machida
H
H
Biology Laboratory, R & D Division, Yamasa Corporation, Choshi, Japan.
Watanabe
Y
Y
Kano
F
F
Sakata
S
S
Kumagai
M
M
Yamaguchi
T
T
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation; D006031:Glycosylation; D018259:Herpesvirus 1, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D007711:Klebsiella pneumoniae / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051381:Rats
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil