Metabolism of the experimental antitumor agent acridine carboxamide in the mouse.
The metabolism of the experimental antitumor agent acridine carboxamide (AC) has been examined in the male BDF1 mouse. [3H]AC was administered at the optimal single intraperitoneal dose for antitumor activity (410 mumol/kg body weight) and the metabolites in urine, bile, and feces characterized using reversed-phase HPLC. In urine (0-24 hr) the main product appears to be a glucuronide, also present in bile, with lesser 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 detected, the major metabolites being two polar species and AC. These polar species are both present in urine and bile where they are increased on incubation with crude beta-glucuronidase. These aglycones have been identified as the 7-hydroxy-9(10H)acridone derivatives of AC and N-monomethyl-AC by [1H]NMR and mass spectrometry. Thus the main pathways of 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 product 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 derivatives may contribute to the slow elimination of AC metabolites.
Robertson
I G
IG
Department of Pharmacology and Clinical Pharmacology, University of Auckland School of Medicine, New Zealand.
Palmer
B D
BD
Paxton
J W
JW
Bland
T J
TJ
D000166:Acridines; D000609:Aminoacridines / Q000378:metabolism* / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005966:Glucuronidase / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction
D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D005966:Glucuronidase