Advertisement

The effect of hepatic uptake on the disappearance of warfarin from the plasma of rats: A kinetic analysis

  • David G. Covell
  • Peter H. Abbrecht
  • Mones Berman
Article

Abstract

To quantify the effects of the liver on the dose dependence of plasma warfarin clearance, an equal number of normal and functionally hepatectomized rats received an intravenous bolus of either 0.01, 0.1, or 1.0 mg/kg body weight of radiolabelled sodium warfarin. Serial samples of plasma and bile collected from each rat during the 1 hr experiment and of hepatic tissue collected at the end of the experiment were analyzed for radioactivity. The disappearance of warfarin from the plasma of hepatectomized rats was not dose dependent and suggested that the apparent dose dependency of plasma warfarin clearance is primarily the result of warfarin's interaction with hepatic tissue. The disappearance of warfarin from the plasma of normal rats was dose dependent with higher doses being cleared less rapidly. This dose dependence, however, was not reflected in the rate of biliary excretion of warfarin's metabolites, which did not show saturation over this dosage range. These results were used to develop a multicompartmental model of warfarin's pharmacokinetics. Plasma warfarin data collected from the hepatectomized rats were used to develop the extrahepatic components of the model, which was then expanded to include hepatic tissues based on data collected from normal rats. To simultaneously fit the plasma, biliary, and hepatic data required that at least two classes of hepatic tissue exchange warfarin with plasma. One tissue exhibited Michaelis-Menten saturation kinetics with Kdand maximum capacity estimated at 1.49E-3μg/ml and 2.72 μg/ml, respectively. The second class exhibited linear exchange kinetics with free plasma warfarin. Warfarin's association with the second class of hepatic tissue leads to its metabolic elimination. Consistent with our experimental findings, the rate of warfarin elimination from the plasma into the bile was linearly related to plasma warfarin concentration. Thus the single hepatic exchange nonlinearity was necessary and sufficient to account for the apparent dose dependency in plasma warfarin's pharmacokinetics. These results suggest that over the range of doses studied, the apparent dose dependent differences in the plasma warfarin concentration profile can be accounted for by saturable hepatic uptake. This mechanism, however, is not related to warfarin's metabolic enzymes, which do not show saturation in the dosage range studied.

Key words

warfarin dose dependent clearance hepatic uptake model kinetics nonlinearity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    K. Takada and G. Levy. Comparative pharmacokinetics of coumarin anticoagulants XLIV: dose-dependent pharmacokinetics of warfarin in rats.J. Pharm. Sci. 69:9–14 (1980).PubMedCrossRefGoogle Scholar
  2. 2.
    K. Takada and G. Levy. Comparative pharmacokinetics of coumarin anticoagulants XLII: concentration-dependent hepatic uptake of warfarin in rats.J. Pharm. Sci. 68:1569–1571 (1979).PubMedCrossRefGoogle Scholar
  3. 3.
    W. D. Wosilait. The relationship between the dose of warfarin, free drug in the plasma, and its elimination in the bile of rats.Res. Commun. Chem. Pathol. Pharmacol. 6:943–950 (1973).PubMedGoogle Scholar
  4. 4.
    R. A. O'Reilly, P. M. Aggeler, and L. S. Leong. Studies on the coumarin anticoagulant drugs: a comparison of the pharmacodynamics of dicoumarol and warfarin in man.Thromb. Diath. Haem. 11:1–22 (1964).Google Scholar
  5. 5.
    R. Nagashima and G. Levy. Comparative pharmacokinetics of coumarin anticoagulants V: kinetics of warfarin elimination in the rat, guinea pig, dog and rhesus monkey compared to man.J. Pharm. Sci. 58:845–849 (1969).PubMedCrossRefGoogle Scholar
  6. 6.
    R. Nagashima, G. Levy, and N. Back. Comparative pharmacokinetics of bishydroxycoumarin elimination in the rat, guinea pig, dog and rhesus monkey.J. Pharm. Sci. 57:68–71 (1968).PubMedCrossRefGoogle Scholar
  7. 7.
    B. B. Brodie, M. Weiner, J. J. Burns, G. Simpson, and E. K. Yale. The physiological disposition of ethyl biscoumacetate (Tromexan) in man and a method for its estimation in biological material.J. Pharmacol. Exp. Ther. 106:453–463 (1952).PubMedGoogle Scholar
  8. 8.
    M. Weiner, S. Shapiro, J. Axelrod, J. R. Cooper, and B. B. Brodie. The physiological disposition of dicoumarol in man.J. Pharmacol. Exp. Ther. 99:409–420 (1950).PubMedGoogle Scholar
  9. 9.
    T. J. Benya and J. G. Wagner. Rapid equilibration of warfarin between rat tissue and plasma.J. Pharmacokin. Biopharm. 3:237–255 (1975).CrossRefGoogle Scholar
  10. 10.
    G. Levy, C. Lai, and A. Yacobi. Comparative pharmacokinetics of coumarin anticoagulants XXXII: interindividual differences in the binding of warfarin and dicoumarol in rat liver and implications for physiological pharmacokinetic modeling.J. Pharm. Sci:67:229–231 (1978).PubMedCrossRefGoogle Scholar
  11. 11.
    W. D. Wosilait and L. L. Eisenbrandt. The effect of oxyphenbutazone on the excreticn of 14-C-warfarin in the bile of rat.Res. Commun. Chem. Pathol. Pharmacol. 4:413–420 (1972).PubMedGoogle Scholar
  12. 12.
    B. B. Brodie. Displacement of one drug by another from carrier or receptor sites.Proc. Roy. Soc. Med. 58:946–955 (1964).Google Scholar
  13. 13.
    R. A. O'Reilly. Studies on the coumarin anticoagulant drugs: interaction of human plasma albumin and warfarin sodium.J. Clin. Inv. 46:829–837 (1967).CrossRefGoogle Scholar
  14. 14.
    K. K. Midha, I. J. McGilveray, and J. K. Cooper. GLC determination of plasma warfarin levels.J. Pharm. Sci. 62:1725–1729 (1974).CrossRefGoogle Scholar
  15. 15.
    R. J. K. Julkunen, M. Kekki, J. J. Himberg, and D. Wahlstrom. Nonlinear multicompartment model for drug binding by extracellular proteins with an application to warfarin.Acta Pharmacol. Toxicol. 38:90–103 (1976).CrossRefGoogle Scholar
  16. 16.
    J. G. Wagner.Fundamentals of Clinical Pharmacokinetics. Drug Intelligence Publications, Hamilton, Ill., 1975.Google Scholar
  17. 17.
    M. Berman and M. Weiss.SAAM Users Manual. DHEW Publication No. (NIH) 79-180 (1981).Google Scholar
  18. 18.
    R. C. Boston, P. C. Greif, and M. Berman. Conversational SAAM-an interactive program for kinetic analysis of biological systems.Computer Programs Biomed. 13:111–119(1981).CrossRefGoogle Scholar
  19. 19.
    M. Kekki, R. J. K. Julkunen, and B. Wahlstrom. Distribution pharmacokinetics of warfarin in the rat, a nonlinear multicompartment model.Naunyn-Schmiedeberg's Arch. Pharmacol. 297:61–73 (1972).CrossRefGoogle Scholar
  20. 20.
    Blood and Other Body Fluids. Biology Handbooks. Fed. Am. Soc. Exp. Biol., Washington D.C., 1963.Google Scholar
  21. 21.
    W. Spector.Handbook of Biological Data. W. B. Saunders, Philadelphia, 1956.Google Scholar
  22. 22.
    S. Garten and W. D. Wosilait. Analysis of the binding of coumarin anticoagulants byhuman serum albumin.Comp. Gen. Pharmacol. 3:83–88 (1972).CrossRefGoogle Scholar
  23. 23.
    A. Yacobi and G. Levy. Comparative pharmacokinetics of coumarin anticoagulants XIV: relationship between protein binding, distribution, and elimination kinetics of warfarin in rats.J. Pharm. Sci. 64:1660–1664 (1975).PubMedCrossRefGoogle Scholar
  24. 24.
    S. Husain, W. D. Wosilait, and L. L. Eisenbrandt. Biliary excretion of 14-C-dicoumarol or its metabolic products in the rat.Life Sci. 10:1–4 (1971).CrossRefGoogle Scholar
  25. 25.
    R. A. O'Reilly, P. M. Aggeler, and L. S. Leong. Studies on the coumarin anticoagulant drugs: the assay of warfarin and its biological applications.Thromb. Diath. Haem. 8:82–95 (1972).Google Scholar
  26. 26.
    W. D. Wosilait. The effect of BSP and rifamycin on the excretion of warfarin in the bile of the rat.Gen. Pharmacol. 8:349–353 (1977).PubMedCrossRefGoogle Scholar
  27. 27.
    W. M. Barker, M. A. Hermadson, and K. P. Link. The metabolism of 4-C-14C sodium warfarin by the rat.J. Pharmacol. Exp. Ther. 171:307–313 (1970).PubMedGoogle Scholar
  28. 28.
    R. Losito and M. A. Rousseau. 14-C-warfarin excretion in the rat.Thromb. Diath. Haem. 27:300–308 (1972).Google Scholar
  29. 29.
    M. L. Powell, B. Pope, G. W. Elmer, and W. F. Trager. Biliary excretion of warfarin metabolites and their metabolism by rat gut flora.Life Sci. 20:171–177 (1977).PubMedCrossRefGoogle Scholar
  30. 30.
    W. F. Ganong.Review of Medical Physiology. Lange Medical Publications, Los Altos, Calif. 1975, p. 425.Google Scholar
  31. 31.
    T. J. Benya and J. G. Wagner. Warfarin binding components of rat liver microsomeslinear and nonlinear.Can. J. Pharm. Sci. 11:69–70 (1975).Google Scholar
  32. 32.
    R. J. K. Julkunen, M. Kekki, and B. Wahlstrom. A model solution for intestinal absorption of warfarin.Arzneim-Forsch./Drug Res. 30(I):264–267 (1980).Google Scholar
  33. 33.
    A. Yacobi and G. Levy. Comparative pharmacokinetics of coumarin anticoagulants XXI: effect of plasma protein binding on distribution kinetics of warfarin in rats.J. Pharm. Sci. 66:567–572 (1980).CrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1983

Authors and Affiliations

  • David G. Covell
    • 1
  • Peter H. Abbrecht
    • 2
  • Mones Berman
    • 1
  1. 1.Laboratory of Mathematical BiologyNational Cancer InstituteBethesda
  2. 2.Departments of Physiology and Internal MedicineUniformed Services University of the Health SciencesBethesda

Personalised recommendations