Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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

Summary

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.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    American Hospital Formulary Service Drug Information (1985) American Society of Hospital Pharmacists, Bethesda, Md, pp 190, 200, 201, 386, 731

  2. 2.

    Atassi G, Briet P, Berthelon JJ, Collonges F (1985) Synthesis and antitumor activity of some 8-substituted-4-oxo-4H-1-benzopyrans. Eur J Med Chem Chim Ther 20: 393

  3. 3.

    Bibby MC, Double JA, Phillips RM, Loadman PM (1987) Factors involved in the anti-cancer activity of the investigational agents IM985 (flavone acetic acid ester) and LM975 (flavone acetic acid). Br J Cancer 55: 159–163

  4. 4.

    Bissery MC, Chabot GG, Corbett TH, Rutkowski K (1986) Flavone acetic acid (FAA; NSC-347512): nonlinearity of area under the concentration X time curves with changing dosage. Proc Am Assoc Cancer Res 27: 282

  5. 5.

    Bissery MC, Valeriote FA, Chabot GG, Crissman JD, Yost C, Corbett TH (1988) Flavone acetic acid (NSC-347512)-induced DNA damage in Glasgow osteogenic sarcoma in vivo. Cancer Res 48: 1279

  6. 6.

    Blanckaert N, Compernolle F, Leroy P, Van Houtte R, Fevery J, Heirwegh KPM (1978) The fate of bilirubin-IX alpha glucuronide in cholestasis and during storage in vitro. Intramolecular rearrangement to positional isomers of glucuronic acid. Biochem J 171: 203

  7. 7.

    Briet P, Berthelon JJ, Collonges F (1982) (4-oxo-4H-1(1)-benzopyran-8-yl)-alkanoic acids, their salts and derivatives, and medicines containing them. European Patent Application Ep—80943 AL, p 34

  8. 8.

    Chabot GG, Bissery MC, Corbett TH, Rutkowski K (1986) Flavone acetic acid (FAA; NSC-347512) pharmacokinetics in mice. Proc Am Assoc Cancer Res 27: 407

  9. 9.

    Chabot GG, Bissery MC, Corbett TH, Rutkowski K (1987) Causes of the nonlinear pharmacokinetics of flavone acetic acid (FAA, NSC 347512) in mice. Proc Am Assoc Cancer Res 28: 436

  10. 10.

    Compernolle F, Van Hees GP, Blanckaert N, Heirwegh KPM (1978) Glucuronic acid conjugates of bilirubin-IX alpha in normal bile compared with post-obstructive bile. Transformation of the 1-O-acylglucuronide into 2-, 3-, and 4-O-acylglucuronides. Biochem J 171: 185

  11. 11.

    Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC, Schabel FM Jr (1975) Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35: 2434

  12. 12.

    Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC, Schabel FM Jr (1977) Evaluation of single agents and combinations of chemotherapeutics agents in mouse colon carcinomas. Cancer 40: 2660

  13. 13.

    Corbett TH, Leopold WR, Dykes DJ, Roberts BJ, Griswold DP Jr, Schabel FM Jr (1982) Toxicity and anticancer activity of a new triazine antifolate (NSC 127755). Cancer Res 42: 1701

  14. 14.

    Corbett TH, Roberts BJ, Trader MW, Laster WR Jr, Griswold DP Jr, Schabel FM Jr (1982) Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents. Cancer Treat Rep 66: 1187

  15. 15.

    Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP Jr, Schabel FM Jr (1984) Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57B1/6 mice. Cancer Res 44: 717

  16. 16.

    Corbett TH, Bissery MC, Wozniak A, Plowman J, Polin L, Tapazoglou E, Dieckman J, Valeriote F (1986) Activity of flavone acetic acid (NSC-347512) against solid tumors of mice. Invest New Drugs 4: 207

  17. 17.

    Gibaldi M, Perrier D (1982) Multicompartment models. In: Swarbrick J (ed) Drugs and the pharmaceutical sciences. Vol 15. Pharmacokinetics. Marcel Dekker, New York, pp 45–111

  18. 18.

    Hackett AM (1986) The metabolism of flavonoid compounds in mammals. In: Cody V, Middleton E Jr, Harborne JB (eds). Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships. Alan R. Liss. New York, pp 177–194

  19. 19.

    Kerr D, Kaye SB, Cassidy J, Bradley C, Harding M, Rankin E, Adams L, Young T, Forrest G, Soukop M (1987) A phase I trial of flavone acetic acid. Proc Am Assoc Cancer Res 28: 224

  20. 20.

    Meffin PJ, Zilm DM, Veenendaal JR (1983) Reduced clofibric acid clearance in renal dysfunction is due to a futile cycle. J Pharmacol Exp Ther 227: 732

  21. 21.

    O'Dwyer PJ, Shoemaker D, Zaharko DS, Grieshaber C, Plowman J, Corbett T, Valeriote F, King SA, Cradock J, Hoth DF, Leyland-Jones B (1987) Flavone acetic acid (LM-975, NSC-347512), a novel antitumor agent. Cancer Chemother Pharmacol 19: 6

  22. 22.

    Osterman CL, Lu K, Raber MN, Newman RA (1986) Preclinical pharmacology of 4-oxo-2-phenyl-4H-1-benzopyran-8-acetic acid (Flavone acetic acid, NSC-347512) in dogs. Proc Am Assoc Cancer Res 27: 405

  23. 23.

    Plowman J, Narayanan VL, Dykes D, Szarvasi E, Briet P, Yoder OC, Paull DK (1986) Flavone acetic acid (NSC-347512), a novel agent with preclinical antitumor activity against the colon adenocarcinoma 38 in mice. Cancer Treat Rep 70: 631

  24. 24.

    Staubus AE, Lyon ME, Grever MR, Wilson HE Jr, Malspeis L (1987) Dose-dependent pharmacokinetics of flavone acetic acid (NSC 347512) in humans. Proc Am Assoc Cancer Res 28: 227

  25. 25.

    Testa B, Jenner P (1976) Drug-metabolizing enzyme systems. In: Swarbrick J (ed). Drug metabolism, chemical and biochemical aspects. Marcel Dekker, New York Basel, pp 273–328

Download references

Author information

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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). https://doi.org/10.1007/BF00254099

Download citation

Keywords

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