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Abstract
1. Metabolism of the experimental antitumour agent N-[2″-(dimethylamino)-ethyl]acridine-4-carboxamide (AC) has been studied in isolated rat hepatocytes using 3H-AC.
2. The major primary metabolites of AC (150 μM) are the 9(10H)acridone, N-oxide and N-monomethyl derivatives. The equivalent 9(10H)acridone derivatives are also formed from AC-N-oxide and N-monomethyl-AC followed by formation of the 7-hydroxy-9(10H)acridone derivatives of AC and N-monomethyl-AC. A similar pattern of metabolism was observed on incubation of AC-N-oxide.
3. Inhibition studies with SKF 525A (250 μM) and methimazole (250 μM) indicate that N-demethylation is mainly catalysed by cytochrome P450 whereas N-oxidation is mediated mainly by flavin-containing monooxygenases. Both primary and secondary acridone formation were also inhibited by SKF 525A as was the back-reduction of AC-N-oxide to AC.
4. These results show that the rat hepatocyte system is a suitable model for further characterization of the metabolism of AC.