Pharmacological disposition and metabolic fate of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine in mice and rats.

2′-Fluoro-5-iodo-1-β-d-arabinofuranosylcytosine (FIAC) is a new potent anti-herpes virus agent which also inhibits the growth of certain human tumor cell lines in vitro . [2-14C]FIAC has been synthesized for the study of pharmacological disposition and metabolic fate. FIAC is deaminated by cytosine nucleoside deaminase at a rate comparable to that of 1-β-d-arabinofuranosyl-cytosine. The deaminated product, 2′-fluoro-5-iodo-1-β-d-arabinofuranosyluracil (FIAU), is, like FIAC, an active antiviral agent. After i.v. injection of [2-14C]FIAC in mice, most of the radioactivity in plasma appears as FIAU. In i.v.-injected rats which lack cytosine nucleoside deaminase, plasma radioactivity is largely present in unchanged FIAC. If mice are pretreated with tetrahydrouridine, an inhibitor of the nucleoside deaminase, plasma radioactivity is mostly FIAC. The radioactivity of [2-14C]FIAC injected i.v. is abundantly excreted in urine, at 63 to 93% of the dose in mice and more than 90% of the dose in rats within 0 to 24 hr. Most of the radioactivity in urine of rats and in mice pretreated with tetrahydrouridine is present in unchanged FIAC; in control mice, most of the radioactivity is found in FIAU. Chromatographic analysis of urine from control mice receiving labeled FIAC has revealed that radioactivity is present in the following nucleosides: FIAC (14.5%); FIAU (73%); 2′-fluoro-5-methyl-1-β-d-arabinofuranosyluracil (5.4%); and 2′-fluoro-1-β-d-arabinofuranosyluracil (2.3%). These metabolites are also present in acidsoluble fractions of mouse blood, small intestine, and liver. Like FIAC and FIAU, 2′-fluoro-5-methyl-1-β-d-arabinofuranosyluracil is a potent antiherpetic agent. Only about 4.3% of the radioactivity of injected [2-14C]FIAC appears in mouse respiratory CO2; degradation to CO2 can be blocked by tetrahydrouridine. Less than 2% of the total radioactivity is excreted in bile in rats. Small amounts of radioactivity are also recovered in feces, mostly in deaminated product. FIAC and FIAU, with a 2′-fluoro substituent in the arabino (“up”) configuration, appear to be less susceptible to metabolic glycosyl cleavage than is the antiherpetic nucleoside, 5-iodo-2′-deoxyuridine. Finally, the radioactivity of [2-14C]FIAC is incorporated into DNA fractions of highly proliferating organs such as intestine, spleen, and thymus, although preliminary results indicate that the substances incorporated are arabinofuranosyl nucleoside metabolites of FIAC.