Metabolism and disposition of 3-amino-1,5-dihydro-5-methyl-1-beta-D-ribofuranosyl-1,4,5,6, 8-pentaazaacenaphthylene in the rat.

Tricyclic nucleoside (TCN, NSC 154020) is a 7-deazapurine nucleoside possessing antitumor activity towards certain tumor cell lines in vitro. In vivo, TCN is readily interconvertible with its 5'-monophosphate ester. The present study demonstrates that TCN is metabolized by rat liver microsomes to a ring-opened bicyclic metabolite with loss of cytotoxicity toward Chinese hamster ovary cells in culture. Metabolism is mediated by hydrogen peroxide generated by the rat liver microsomes but is not dependent on cytochrome P-450. Isolated hepatocytes prepared from rat do not form detectable amounts of the ring-opened bicyclic metabolite. Unchanged TCN and the ring-opened bicyclic metabolite are excreted in the bile of rats with a cannulated bile duct, comprising 42 and 12% of an i.v. dose of TCN in 8 hr, respectively. The ring-opened bicyclic metabolite is not formed by red blood cells in vitro and could not be detected in blood in vivo. The fact that the ring-opened bicyclic metabolite appears in bile suggests that liver cells not present or not active in isolated hepatocyte preparations might produce the metabolite. Alternatively, the metabolite might be formed directly from TCN in bile, perhaps by hydrogen peroxide excreted into bile. In vivo, 56% of radiolabel was found in the upper and lower gastrointestinal tract and the feces 24 hr after an i.p. or i.v. dose of 100 mg of [5-methyl-14C]TCN/sq m. Urinary excretion of radiolabel was 21% of the dose of [14C]TCN in 24 hr. Biliary excretion of radiolabel was 65% of the dose of [14C]TCN in 8 hr. The fraction of radioactivity undergoing enterohepatic cycling with reabsorption from the gastrointestinal tract after excretion in bile is 84%.