Abstract
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 aliphaticN-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 aCmax of 1171 μg/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 μg/h/ml at 20 mg/kg to 247 μg/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/z429.5 (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 andCmax at 200 mg/kg being 3.54 μg/h/ml and 3.7 μg/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.
Footnotes
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Send reprint requests to: Dr. Paul Loadman, Cancer Research Unit, University of Bradford, Bradford BD7 1DP, UK. E-mail:P.M.Loadman{at}Bradford.ac.uk
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This work was supported by War on Cancer, Bradford, and the Cancer Research Campaign, UK.
- Abbreviations used are::
- MTD
- maximum tolerated dose
- AQ4N
- 1,4-bis- {[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione
- AQ4M, 1-{[2-(dimethylamino-N-oxide)ethyl]amino}-4-{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione
- AQ4, 1,4-bis-{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione
- AUC
- area under the plasma concentration versus time curve
- HPLC
- high-performance liquid chromatography
- MS
- mass spectroscopy
- Received June 21, 2000.
- Accepted December 15, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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