P. Schofield, I. Robertson, J. Paxton
1999
Citations
1
Influential Citations
29
Citations
Quality indicators
Journal
Cancer Chemotherapy and Pharmacology
Abstract
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-mono- methyl-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.