A preclinical pharmacokinetic study of the bioreductive drug AQ4N

AQ4N (1,4-bis-[[2-(dimethylamino-N-oxide)ethyl]amino]5,8-dihydroxyanthracene-9,10-dione) is in a class of bioreductive agents incorporating the aliphatic N-oxide functionality and is well documented as a very effective enhancer of radiotherapy and chemotherapy. The compound is shortly to enter Phase I clinical trials in the United Kingdom, and this study describes the preclinical pharmacokinetics and metabolism of AQ4N in mice. AQ4N was administered by i.v. injection at doses of 200, 100, and 20 mg/kg and was quantified by high-performance liquid chromatography and liquid chromatography/mass spectroscopy. There was a linear increase in the maximum plasma concentration (Cmax) proportional to dose with a Cmax of 1171 microg/ml at the maximum tolerated dose of 200 mg/kg. The area under plasma concentration versus time curve (AUC) increased disproportionately with dose from 14.1 microg/h/ml at 20 mg/kg to 247 microg/h/ml at 200 mg/kg with a subsequent decrease in clearance. Terminal elimination half-lives ranged from 0.64 to 0.83 h. The spectra of the two major metabolites matched those from authentic standards with the molecular ions [M + H]+ being detected at m/z 445.4 (AQ4N), m/z 429.5 (AQ4 mono-N-oxide) and m/z 413.5 (AQ4). Only low concentrations of the toxic metabolite (AQ4) were detected in plasma at all three doses, with the AUC and Cmax at 200 mg/kg being 3.54 microg/h/ml and 3.7 microg/ml, respectively, representing <2% of AQ4N. Concentrations of the intermediate AQ4 M represented 8, 10, and 18% of those for AQ4N at the doses of 20,100, and 200 mg/kg. The concentrations necessary for a therapeutic response in vivo have been described in this pharmacokinetic study.