Biotransformation and elimination of [2-14C]-1-(2-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine in immunosuppressed patients with herpesvirus infections.
The metabolism of the drug [2-14C]-1-(2'-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine (FIAC), a potent inhibitor of herpesvirus replication, was studied in immunosuppressed patients with herpesvirus infections. FIAC was administered intravenously by 15-min infusion and by mouth 24 h later to four patients at doses of 50 or 100 mg/m2. FIAC was cleared from the plasma primarily by biotransformation in liver, kidney, and peripheral blood, with a terminal-phase half-life of 0.92 to 1.80 h (mean, 1.36 h) after intravenous administration. The area under the concentration-time curve from zero to infinity (AUC0-infinity) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUC0-infinity for total radioactivity. 1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was the major metabolite; the AUC0-infinity for FIAU was 54.3 to 72.5% (mean, 63.4%) of the AUC0-infinity for total radioactivity. The terminal-phase half-life for FIAU was 3.32 to 4.49 h (mean, 3.91 h); FIAU was cleared from plasma by renal elimination and further biotransformation. lesser amounts of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)cytosine, the glucuronide conjugates of these metabolites, and the glucuronide conjugates of FIAC and FIAU were also formed. A comparison of the AUC0-infinity for total radioactivity after intravenous and oral administration suggested that nearly all of the oral dose was absorbed. Plasma levels of FIAU, also a potent inhibitor of herpesvirus replication in vitro, exceeded the 50% effective dose for herpes simplex virus and varicella-zoster virus as late as 12 h after administration of FIAC.
Feinberg
A
A
Leyland-Jones
B
B
Fanucchi
M P
MP
Hancock
C
C
Fox
J J
JJ
Watanabe
K A
KA
Vidal
P M
PM
Williams
L
L
Young
C W
CW
Philips
F S
FS
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006566:Herpesviridae Infections / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000032:analysis
D000998:Antiviral Agents; D005965:Glucuronates; D003561:Cytarabine; C026023:fiacitabine