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Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice


Flavone acetic acid (FAA) is a novel antitumor agent with broad solid-tumor activity. However, this drug has shown a steep dose-response curve in preclinical trials, with a narrow sublethal window of efficacy. To investigate this threshold behavior, we studied various aspects of FAA pharmacology in mice after i.v. administration. Mice bearing advanced-stage s.c. colon 38 adenocarcinoma were treated at four dose levels (39, 65, 108, and 180 mg/kg), and only the highest dose produced significant antitumor activity, showing a steep dose-response curve. Using an HPLC assay, FAA pharmacokinetics in both plasma and tumors were found to be dose-dependent. As the dose increased, there was a decrease in both total body clearance and volume of distribution at steady state. The increase in tumor area under the curve (AUC) was more pronounced than the corresponding increase in plasma AUC, showing a better tumor exposure to FAA at high doses. The distribution of FAA in normal tissues showed a short-term retention in the liver and kidneys; low concentrations were observed in the heart, spleen, and brain, with some retention in the latter. The highest FAA concentrations were found in the gastrointestinal (GI) tract, mainly in the duodenum, suggesting an important biliary excretion of the drug. Various possible causes of FAA nonlinear pharmacokinetics were investigated. Serum protein binding was high (79%) and remained constant up to 100 μg/ml, but decreased thereafter at higher FAA concentrations, e.g., 76% at 500 μg/ml and 64% at 1,000 μg/ml. Urinary and biliary clearances were dose-dependent and decreased 5- and 9-fold, from the 39- to the 180-mg/kg dose levels, respectively. A direct assessment of FAA enterohepatic circulation using intercannulated mice showed that 27% of the plasma AUC was accounted for by enterohepatic circulation. FAA acyl glucuronide was identified as the major metabolite in mice and was found to contribute to the nonlinear pharmacokinetics due to its facile hydrolysis under physiological conditions, regenerating FAA. In conclusion, the steep FAA dose-response curve was found to be caused by dose-dependent pharmacokinetics in mice. The nonlinear pharmacokinetics of this drug was attributed to a dose-dependent decrease in both urinary and biliary clearances, concentration-dependent serum protein binding, enterohepatic circulation, and the instability of FAA acyl glucuronide under physiological conditions, forming a futile cycle. The distribution data also suggested possible tissue targets for anticancer efficacy and/or toxicity that could be useful in designing clinical studies.

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Correspondence to Guy G. Chabot.

Additional information

This work was supported in part by the Wayne State University Ben Kasle Trust Fund for Cancer Research, by Public Health Service grants CA-43886 and CA-42449 from the National Cancer Institute, and by the Harper Medical Staff Trust Fund. Preliminary reports of this study were presented in abstract form [4, 8, 9]. Offprint requests to: Guy G. Chabot, Institut Gustave-Roussy, Pavillon de Recherche, 39 rue Camille Desmoulins, F-94805 Villejuif Cedex, France

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Chabot, G.G., Bissery, M., Corbett, T.H. et al. Pharmacodynamics and causes of dose-dependent pharmacokinetics of flavone-8-acetic acid (LM-975; NSC-347512) in mice. Cancer Chemother. Pharmacol. 24, 15–22 (1989).

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  • Biliary Excretion
  • Total Body Clearance
  • Enterohepatic Circulation
  • HPLC Assay
  • Preclinical Trial