Pharmacological Disposition and Metabolic Fate of 2′-Fluoro-5-iodo-1-β-d-arabinofuranosylcytosine in Mice and Rats

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