RAT HEPATOCYTE-MEDIATED METABOLISM OF THE EXPERIMENTAL ANTITUMOR AGENT N-[2'-(DIMETHYLAMINO)ETHYL]ACRIDINE-4-CARBOXAMIDE

1. Metabolism of the experimental antitumour agent N-[2'-(dimethylamin o)-ethyl]acridine-4-carboxamide (AC) has been studied in isolated rat hepatocytes using H-3-AC. 2. The major primary metabolites of AC (150 mum) are the 9 (10H) acridone, N-oxide and N-monomethyl derivatives. T he equivalent 9(10H)acridone derivatives are also formed from AC-N-oxi de and N-monomethyl-AC followed by formation of the 7-hydroxy-9(10H)ac ridone derivatives of AC and N-monomethyl-AC. A similar pattern of met abolism was observed on incubation of AC-N-oxide. 3. Inhibition studie s with SKF 525A (250 mum) and methimazole (250 mum) indicate that N-de methylation 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 wa s the back-reduction of AC-N-oxide to AC. 4. These results show that t he rat hepatocyte system is a suitable model for further characterizat ion of the metabolism of AC.