METABOLIC STUDIES WITH 5-FLUOROCYTOSINE-6-C-14 IN MOUSE, RAT, RABBIT, DOG AND MAN

Metabolism of 5-fluorocytosine-6-14C (5-FC) was studied in mice, rats, rabbits and dogs after oral and s.c., single and repeated administration. In the urines of all species, intact 5-FC accounted for more than 90% of the total radioactivity at any time of the various treatment schedules. The average proportion of the urinary metabolites was around 5% in dogs, 3% in rabbits, 2.5% in rats and 2% in mice of the total radioactivity. At repeated dosage, there was an increase of metabolites in mice but a decrease in rats treated s.c. Neither increase nor decrease was observed in rabbits (treated orally) and dogs. Two metabolites were identified, .alpha.-fluoro-.beta.-ureido-propionic acid (FUPA) and .alpha.-fluoro-.beta.-alanine, the latter occurring mainly after oral treatment. These compounds represent probably that part of 5-FC which was deaminated to 5-fluorouracil (5-FU) or directly to 5-fluorodihydrouracil. FUPA was the only metabolite found in the urines collected from 4 of 5 human volunteers during the 1st 12 h after single oral administration of 3.5 g of the radiolabeled drug. Its maximum proportion was 1.1% of the total radioactivity. No metabolites were detected in the urine neither of the 5th volunteer nor in those of 3 mycosis patients who were given the radioactive dose after they received regular chemotherapy with unlabeled 5-FC (150 mg/kg per day) for at least 2 wk. The sensitivity threshold of the method was 0.1-0.4% of the total radioactivity. One of the patients had developed thrombocytopenia which was probably due to 5-FC chemotherapy. The symptoms of 5-FC intolerance were in most of the examined species similar to those observed with 5-FU. No quantitative correlation between proportion of metabolites and 5-FC toxicity is apparent except that man is the species in which both metabolism and toxicity are the lowest. It has not been proved yet that 5-FC intolerance occurring in a small percentage of patients receiving 5-FC chemotherapy (mainly leukopenia, thrombocytopenia) results from conversion to 5-FU.