METABOLISM OF THE EXPERIMENTAL ANTITUMOR AGENT ACRIDINE CARBOXAMIDE IN THE MOUSE

The metabolism of the experimental antitumor agent acridine carboxamid e (AC) has been examined in the male BDF1 mouse. [H-3]AC was administe red at the optimal single intraperitoneal dose for antitumor activity (410 mumol/kg body weight) and the metabolites in urine, bile, and fec es characterized using reversed-phase HPLC. In urine (0-24 hr) the mai n product appears to be a glucuronide, also present in bile, with less er amounts of AC, AC-N-oxide, and at least 10 minor products. Biliary excretion of AC metabolites (examined after removal of the gallbladder at the appropriate times) is greatest at 1-2 hr after treatment when at least 14 products are detected, including AC, AC-N-oxide, and other products with UV/visible spectra characteristic of ring hydroxylated and/or acridone derivatives. In feces (0-24 hr) no AC-N-oxide is detec ted, the major metabolites being two polar species and AC. These polar species are both present in urine and bile where they are increased o n incubation with crude beta-glucuronidase. These aglycones have been identified as the 7-hydroxy-g(10H)acridone derivatives of AC and N-mon omethyl-AC by [H-3]NMR and mass spectrometry. Thus the main pathways o f elimination of AC appear to be 1) N-oxidation and 2) 9(10H)acridone formation plus 7-hydroxylation of both AC and its N-demethylated produ ct followed by glucuronidation. Reduction of AC-N-oxide in the gut may allow reabsorption of AC. Both the back-reduction and reabsorption of AC, and enterohepatic circulation of the 7-hydroxyacridone derivative s may contribute to the slow elimination of AC metabolites.