Metabolism and excretion of nitrofurothiazole bladder carcinogens

Nitrofurothiazoles such as 2-amino-4-(5-nitro-2-furyl) thiazole (ANFT) and N-formylated ANFT (FANFT) are model compounds used in the study of chemical carcinogenesis. FANFT is a more potent uroepithelial carcinogen than ANFT but previous studies have shown extensive deformylation of FANFT to ANFT in vivo and ANFT to be the putative proximate carcinogen. To investigate this paradox, disposition of radiolabeled FANFT and ANFT was determined in rats prepared for clearance experiments. After 2 hr, 27.3 +/- 2.1% of recovered ANFT was excreted in urine compared to 44.2 +/- 1.8% of FANFT (P less than .001). In addition, approximately 20% of both FANFT and ANFT were excreted in bile after 2 hr. The disposition of nonradiolabeled FANFT and ANFT was also determined. The urinary excretion rate for ANFT with i.v. ANFT administration was 0.9 +/- 0.1 nmol/min. Following i.v. FANFT administration, the urinary excretion rate for ANFT was 49.7 +/- 8.6 nmol/min (P less than .001). The elimination half-lives were 23 +/- 3 and less than 5 min, for ANFT and FANFT, respectively. The differences in renal handling of ANFT and FANFT could not be accounted for by differences in protein binding. Large differences were found in urinary metabolite excretion between FANFT and ANFT administration. These results demonstrate deformylation dependent excretion (renal metabolic/excretory coupling) exists for FANFT resulting in much higher concentrations of ANFT reaching the urinary tract than when ANFT only is administered. Biliary excretion accounts for significant early clearance of both ANFT and FANFT. Renal metabolic/excretory coupling may explain the difference in uroepithelial carcinogenicity between FANFT and ANFT.