Metabolism of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in cancer patients undergoing a phase I clinical trial.
N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is an experimental antitumour agent that has just completed phase I clinical trials in New Zealand and the United Kingdom. Urine (0-72 h) was analysed from 20 patients receiving DACA infused over 3 h (dose range 60-1000 mg/m2, the latter being the highest dose achieved in the trial). Aliquots were analysed for DACA and its metabolites by high-performance liquid chromatography (HPLC). Over 72 h, 44+/-5% (range 20-60%) of the dose was recovered in the urine, with 0.8+/-0.3% (range 0-3.1%) occurring as DACA. The major urinary metabolite was DACA-N-oxide-9(10H)acridone, accounting for 34+/-3% of the dose. Minor metabolites were identified as N-monomethyl-DACA-9(10H)acridone (2.0+/-0.5%), DACA-9(10H)acridone (3.3+/-0.5%), N-monomethyl-DACA (0.2+/-0.1%) and DACA-N-oxide (0.5+/-0.1%). No ring-hydroxylated metabolite was detected. The urinary excretion of metabolites was greatest over 0-6 h in most patients. The composition of urinary metabolites was also independent of the delivered dose. Plasma was sampled at intervals throughout the infusion and at time points up to 48 h post-administration. The major plasma metabolites observed were DACA-9(10H)acridone and DACA-N-oxide-9(10H)acridone. These results indicate that, based on urinary excreted metabolites, the major biotransformation reactions for DACA in humans involve N-oxidation of the tertiary amine side chain and acridone formation, both of which appear to be detoxication reactions.
Schofield
P C
PC
Department of Pharmacology and Clinical Pharmacology, The University of Auckland School of Medicine, New Zealand.
Robertson
I G
IG
Paxton
J W
JW
McCrystal
M R
MR
Evans
B D
BD
Kestell
P
P
Baguley
B C
BC
D000166:Acridines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy
D000166:Acridines; D000970:Antineoplastic Agents; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide