Binding of non-steroid anti-inflammatory drugs and warfarin to liver tissue of rabbits in vitro

  • Christine Tesseromatis
  • Buckard Fichtl
  • Hermann Kurz
Original Papers


Liver slices (10mm 0,1mm thickness) were incubated at 37° C in drug solutions up to 360 min. The drugs were dissolved in Ringer solution of pH 7.0. After 60, 180, 240 and 360 min each drug concentration was determined in the incubation fluid. For all drugs tested equilibrium was obtained after 240 min. The amount of drug taken up by the slices was calculated from the difference to initial concentration. In parallel, samples of the slices were homogenized together with their incubation fluids after the same incubation intervals. The free concentration was determined by ultrafiltration. For warfarin and several non-steroid anti-inflammatory drugs (NSAID), i.e. acetylsalicylic acid, ibuprofen, ketoprofen and oxyphenbutazone, there was no difference between the free drug concentrations in the homogenized and in non-homogenized samples.

This suggests that the binding of these drugs to’ liver tissue was not altered by homogenization. Further was studied whether NSAIDS interfere with binding of warfarin to liver tissue. Acetylsalicylic acid, flurbiprofen, ibuprofen, ketoprofen, oxyphenbutazone and proquazon markedly increased the free concentration of warfarin both in liver slices and homogenates (p<0.01). The extent of displacement did not differ between slices and homogenates.


Protein-binding Liver tissue Non-Steroid Anti-Inflammatory acetylsalicylic acid flurbiprofen ketoprofen ibuprofen oxyphenbutazone proquazon warfarin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Levy, G., Lai, CM., Jacobi, A. (1978): Comparative Pharmacokinetics of Coumarin Anticoagulants XXXII Interindividual Differences in Binding of Warfarin and Dicumarol in Rat Liver and Implications for Physiological Pharmacokinetic Modeling. J. Pharm. Sci.67 (2), 229–231.CrossRefPubMedGoogle Scholar
  2. 2.
    Shen, D., Gibaldi, M. (1974): Critical evaluation of use of effective protein fractions in developing pharmacokinetic models for drug distribution. J. Pharm. Sci.63, 1698–1703.CrossRefPubMedGoogle Scholar
  3. 3.
    Wilkinson, G.R. (1975): Pharmacokinetics of drug disposition; hemodynamic considerations. Ann. Rev. Pharmacol.15, 11–27.CrossRefPubMedGoogle Scholar
  4. 4.
    Goodman, L.S. and Gilman, A. (1980): The Pharmacological basis of Therapeutics.6 Ed. p. 11.Google Scholar
  5. 5.
    Jähnchen, E., Wingard, L.B., Levy, G. (1973): Effect of Phenylbutazone on the distribution, elimination and anticoagulant action of dicumarol in rats. J. Pharmacol. Exp. Ther.187, 176–84.PubMedGoogle Scholar
  6. 6.
    Koch-Wesser, J., Sellers, E.M. (1971): Drug interactions with coumarin anticoagulants. N. Eng. J. Med.285, 487–98.CrossRefGoogle Scholar
  7. 7.
    O’Reilly, A.A., and Levy, G. (1970): Pharmacokinetic analysis of potentiating effect of phenylbutazone on anticoagulant action of warfarin in man. J. Pharm. Sci.59, 1258–1261.CrossRefPubMedGoogle Scholar
  8. 8.
    O’Reilly, R.A., Goulart, D.A. (1981): Comparative interaction sulfinpyrazone and phenylbutazone with racemic warfarin. Alteration in vivo of free fraction of plasma warfarin. J. Pharmacol. Exp. Ther.219, 691–94.PubMedGoogle Scholar
  9. 9.
    Kurz, H. (1961): Ein Gerät zur Herstellung dünner Schnitte aus frischem tiereschem Gewebe. Z. ges. exp. Med.134, 304–309.CrossRefPubMedGoogle Scholar
  10. 10.
    Kurz, H. Trunk, H., Weitz. B., (1977): Evaluation of methods to determine protein binding of drugs. Arzneim. Forsch.27 (II), 7, 1373–1380.Google Scholar
  11. 11.
    Hewitt, E.J. and Nicholas, D.J.D. (1963): Metabolic Inhibitors. A comprehensive Theatisse. Vol. II Academic Press. A.P.N. York, London.Google Scholar
  12. 12.
    Ducombe, G.W. (1963): The colorometric Micro-Determination of Long Chain Fatty Acids. Biochem. J. 88, 7–10.Google Scholar
  13. 13.
    Fujise, H. (1977): A simple and sensitive colorometric determination of ibuprofen from plasma and urine in dogs after dosing. Jap. J. vet. Sci.39, 671–73.Google Scholar
  14. 14.
    Ballerini, R., Cambi, A., Del Soldato, P., Melani F., Meli A. (1979): Determination of ketoprofen by direct injection of deproteinized body fluids into a high Pressure Liquid Chromatographic System. J. Pharm. Sci.68, 366–368.CrossRefPubMedGoogle Scholar
  15. 15.
    Bums, J.J., Rose, R.K., Chenkin, T., Gollman, A., Scurlet, A., Brodie, B.B. (1953): The physiological disposition of phenylbutazone in man and a method for its estimation in biological material. J. Pharmacol, exp. Ther.215, 248–53.Google Scholar
  16. 16.
    Fichtl, B., Bondy, B. Kurz, H. (1980): Binding of drugs to muscle tissue: Dependence on drug concentration and lipid content of tissue. J. Pharmacol. Exp. Ther.215, 248–253.PubMedGoogle Scholar
  17. 17.
    Fichtl, B., Kurz, H., (1980): Does determination of drug binding in homogenized tissue reflect binding in the intact organ. Arch. Pharmacol. 311 R3.Google Scholar
  18. 18.
    Filous, N., Fichtl, B., Kurz, H. (1976): Binding of drugs to muscle tissue. Arch. Pharmacol. 293 R 46.Google Scholar
  19. 19.
    Bickel, M.H., Steele, J.W. (1974): Binding of basic and acidic drugs to the rat tissue subcellular fractions. Chem. Biol. Interactions8, 151–62.CrossRefGoogle Scholar
  20. 20.
    Kurz. H. (1966): Die Permeation von Giften in die Leber. Eingeschaften der Zellmembran. Arch. Pharmac. (Naunym-Schmied.) 254, 33–44.Google Scholar
  21. 21.
    Vasko, M.R., Hug, C.C. (1972): Is the uptake of narcotic analgesics by célébrai cortical slices mediated in part by active transport? J. Pharm. Pharmac.25, 180–83.Google Scholar
  22. 22.
    Whitsett, T.L., Dayton, P.G. and McNay, J.L. (1971): The effect of hepatic blood flow on the hepatic removal rate of oxyphenbutazone in the dog. J. Pharmacol. Exp. Ther.17, 246–55.Google Scholar
  23. 23.
    Schanker, L.S., Morrison, A.S. (1965): Physiological disposition of guanethidine in the rat and its uptake by heart slices. In. J. Neuropharmacol. 4, 27–29.CrossRefGoogle Scholar
  24. 24.
    Wosilait, W.D. (1968): The accumulation and distribution of dicumarol in rat liver slices. Biochem. Pharmacol.17, 429–437.CrossRefPubMedGoogle Scholar
  25. 25.
    DiSanto, A.R., and Wagner, J.C. (1972): Potential Erroneous Assignment of Non-Linear Data to classical linear two Compartiment open Model. J. Pharm. Sci.61, 552–55.CrossRefPubMedGoogle Scholar
  26. 26.
    Sellers, E.M. (1978): The clinical importance of interactions based on displacement of protein bound drugs. Pro. Int. Congr. Pharm.2, 896.Google Scholar
  27. 27.
    Avery, S.C. (1980): Drug Treatment Principles and Practice of clinical Pharmacology and Therapeutics. 2nd Ed ADIS press Sydney and N. York, Churchill Livingstone, p. 244, 908–910.Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • Christine Tesseromatis
    • 1
  • Buckard Fichtl
    • 1
  • Hermann Kurz
    • 1
  1. 1.Department of PharmacologyUniversity of MunichMunichFederal Republic of Germany

Personalised recommendations