BIOTRANSFORMATION AND ELIMINATION OF [2-C-14]-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 i.v. by 15-min infusion and by mouth 24 h later to 4 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 0.92-1.80 h (mean, 1.36 h) after i.v. administration. The area under the concentration-time curve from zero to infinity (AUCo-.infin.) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUCo-.infin. for total radioactivity. 1-(2''-Deoxy-2''-fluoro-.beta.-D-arabinofuranosyl-5-iodouracil (FIAU) was the major metabolite; the AUCo-.infin. for FIAU was 54.3-72.5% (mean, 63.4%) of the AUCo-.infin. for total radioactivity. The terminal-phase half-life for FIAU was 3.32-4.49 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 AUCo-.infin. for total radioactivity after i.v. 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.