Rat hepatocyte-mediated metabolism of the experimental anti-tumour agent N-[2'-(dimethylamino)ethyl]acridine-4-carboxamide.
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 microM) 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 microM) and methimazole (250 microM) 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.
Schlemper
B
B
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
Siegers
D J
DJ
Paxton
J W
JW
Robertson
I G
IG
D000166:Acridines; D000609:Aminoacridines / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; D005965:Glucuronates; D008713:Methimazole; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen