Loadman P M, Swaine D J, Bibby M C, Welham K J, Patterson L H
Cancer Research Unit, University of Bradford, Bradford, United Kingdom.
Drug Metab Dispos. 2001 Apr;29(4 Pt 1):422-6.
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.
AQ4N（1,4 - 双[[2 - （二甲氨基 - N - 氧化物）乙基]氨基] - 5,8 - 二羟基蒽醌 - 9,10 - 二酮）属于一类含有脂肪族N - 氧化物官能团的生物还原剂，并且有充分文献记载其是放疗和化疗的一种非常有效的增效剂。该化合物即将在英国进入I期临床试验，本研究描述了AQ4N在小鼠体内的临床前药代动力学和代谢情况。通过静脉注射给予小鼠200、100和20mg/kg剂量的AQ4N，并通过高效液相色谱法和液相色谱/质谱法进行定量。最大血浆浓度（Cmax）随剂量呈线性增加，在200mg/kg的最大耐受剂量下Cmax为1171μg/ml。血浆浓度 - 时间曲线下面积（AUC）随剂量不成比例增加，从20mg/kg时的14.1μg/h/ml增加到200mg/kg时的247μg/h/ml，随后清除率降低。终末消除半衰期范围为0.64至0.83小时。两种主要代谢物的光谱与来自真实标准品的光谱匹配，分子离子[M + H]+在m/z 445.4（AQ4N）、m/z 429.5（AQ4单 - N - 氧化物）和m/z 413.5（AQ4）处被检测到。在所有三个剂量下，血浆中仅检测到低浓度的有毒代谢物（AQ4），200mg/kg时的AUC和Cmax分别为3.54μg/h/ml和3.7μg/ml，占AQ4N的比例小于2%。中间代谢物AQ4 M的浓度在20、100和200mg/kg剂量下分别占AQ4N浓度的8%、10%和18%。本药代动力学研究描述了体内产生治疗反应所需的浓度。
