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Plasma pharmacokinetics of the antitumour agents 5,6-dimethylxanthenone-4-acetic acid, xanthenone-4-acetic acid and flavone-8-acetic acid in mice

  • Original Articles
  • Plasma Pharmacokinetics, Antitumor Agent, Flavone-8-Acetic Acid
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Summary

Although the antitumour agent flavone-8-acetic acid (FAA) exhibits remarkable activity against murine solid tumours, its clinical use has a number of pharmacological drawbacks, including low dose potency and dose-dependent pharmacokinetics. Xanthenone-4-acetic acid (XAA) and its 5,6-dimethyl derivative (5,6-MeXAA) were synthesised during a search for better analogues of FAA. The maximal tolerated doses (MTDs) of 5,6-MeXAA, XAA and FAA in BDF1 mice were 99, 1,090 and 1,300 μmol/kg, respectively. At the MTD, 5,6-MeXAA displayed the following pharmacokinetic properties: maximal plasma concentration, 600 μM; mean residence time, 4.9 h; AUC, 2,400 μmol h l−1; and volume of steady-state distribution, 0.2 l/kg. All compounds displayed nonlinear elimination kinetics at the MTD, but when the logarithm of the AUC was plotted against that of the delivered dose, the slope of the regression line for 5,6-MeXAA was found to be 1.2 as opposed to 1.4 for XAA and 1.98 for FAA. 5,6-MeXAA thus showed only a slight deviation from dose-independent kinetics. 5,6-MeXAA bound to plasma proteins in a manner similar to that exhibited by FAA, although the plasma concentration of free drug was lower for the former than for the latter. As a consequence, the calculated maximal free drug concentration for 5,6-MeXAA in plasma was 23 times lower than that for FAA.

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Author notes

  1. Mark J. McKeage

    Present address: Department of Biochemical Pharmacology, Institute of Cancer Research, Block E, Cotswold Road, Belmont, SM2 5NG, Sutton, Surrey, UK

Authors and Affiliations

  1. Cancer Research Laboratory, University of Auckland Medical School, Private Bag, Auckland, New Zealand

    Mark J. McKeage, Philip Kestell, William A. Denny & Bruce C. Baguley

Authors
  1. Mark J. McKeage
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  2. Philip Kestell
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  3. William A. Denny
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  4. Bruce C. Baguley
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Additional information

This work was supported by a Todd Foundation Clinical Oncology Research Training Fellowship, by the Medical Research Council of New Zealand and by the Cancer Society of New Zealand

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McKeage, M.J., Kestell, P., Denny, W.A. et al. Plasma pharmacokinetics of the antitumour agents 5,6-dimethylxanthenone-4-acetic acid, xanthenone-4-acetic acid and flavone-8-acetic acid in mice. Cancer Chemother. Pharmacol. 28, 409–413 (1991). https://doi.org/10.1007/BF00685815

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  • DOI: https://doi.org/10.1007/BF00685815

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