Abstract
Experimental work on heparin has indicated that its half-life increases with dose. Two models to describe heparin's pharmacokinetic behavior are proposed, and the parameters in the models are fitted to experimental data. Both models exhibit an apparent firstorder decay with a “halflife” that increases with dose. It is shown that, even though both models exhibit a bolus half-life of from 1 to 2 hr, over 2 days can be required for true steadystate conditions to be achieved in these models when a constant intravenous infusion of drug is given. The clinical implications of these models are discussed. Suggestions are made for further research on heparin kinetics.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
T. J. McAvoy, The biologic halflife of heparin.Clin. Pharmacol. Ther. 25:372–379 (1979).
J. W. Estes, E. W. Pelikan, and E. Kruger-Thiemer. A retrospective study of the pharmacokinetics of heparin.Clin. Pharmacol. Ther. 10:329–337 (1969).
J. W. Estes. The kinetics of heparin.N. Y. Acad. Sci 179:187–204 (1971).
J. W. Estes. The heterogeneity of the anticoagulant response to heparin.J. Clin. Pathol. 25:45–48 (1972).
J. W. Estes and P. F. Poulin. Pharmacokinetics of heparin: Distribution and elimination.Thromb. Diath. Haemorrh. 33:26–37 (1974).
P. Olsson, H. Lagergren, and S. Ek. The elimination from plasma of intravenous heparin.Acta. Med. Scand. 173:619–630 (1963).
E. Jahnchen and G. Levy. Inhibition of phenylbutazone elimination by its metabolite oxyphenbutazone.Proc. Soc. Exp. Biol. 141:963–965 (1965).
J. J. Ashley and G. Levy. Inhibition of diphenylhydantoin elimination by its major metabolite.Res. Commun. Chem. Pathol. Pharmacol. 4:297–306 (1972).
G. Levy and J. J. Ashley. Effect of an inhibitor of glucuronide formation on the elimination kinetics of diphenylhydantoin in rats.J. Pharm. Sci. 62:161–162 (1973).
R. A. O'Reilly, P. M. Aggeler, and L. S. Leong. Studies on the coumarin anticoagulant drugs: A comparison of the pharmacodynamics of dicumarol and warfarin in man.Thromb. Diath. Haemorrh. 11:1–22 (1964).
P. G. Dayton, S. A. Cucinell, M. Weiss, and J. M. Perel. Dosedependence of drug plasma level decline in dogs.J. Pharmacol. Exp. Ther. 158:305–316 (1967).
D. Perrier, J. J. Ashley, and G. Levy. Effect of product inhibition on kinetics of drug elimination.J. Pharmacokin. Biopharm. 1:231–242 (1973).
L. B. Jaques and H. J. Bell. Determination of heparin.Methods Biochem. Anal. 7:253–309 (1959).
F. C. Monkhouse. Physiological factors concerned with the removal of injected heparin from the circulating blood.Am. J. Physiol. 178:223–228 (1954).
B. Benacerraf and P. Miescher. Bacterial phagocytosis by the reticuloendothelial systemin vivo under different immune conditions.N. Y. Acad. Sci. 88:184–195 (1960).
I. H. Segel.Enzyme Kinetics, Wiley, New York, 1975, Chap. 8.
J. W. Estes. The fate of heparin in the body.Curr. Ther. Res. 18:45–57 (1975).
D. Z. D'Argenio and A. Schumitzky. A program package for simulation and parameter estimation in pharmacokinetic systems.Computer Prog. Med. 9:115–134 (1979).
C. V. Moore. Diseases of the white blood cells and reticuloendothelial system. InCecil-Loeb Textbook of Medicine, 13th ed., Saunders, Philadelphia, 1971.
A. J. Vander, J. H. Sherman, and D. S. Luciano.Human Physiology. McGraw-Hill, New York, 1975, p. 228.
R. J. Ignoffo. Correspondence on heparin half-life in normal and impaired renal function.Clin. Pharmacol. Ther. 17:249–250 (1975).
D. P. Thomas. Treatment of pumonary embolic disease.New Engl. J. Med. 273:885–892 (1965).
V. Gurewich. Some guidelines for heparin therapy of venous thromboembolic disease.J. Am. Med. Assoc. 199:116–118 (1967).
E. Sullivan. Heparin in treatment of venous thromboembolic disease: Administration, control, and results.Med. J. Aust. 2:153 (1968).
P. J. Perry, G. R. Herron, and J. C. King. Heparin halflife in normal and impaired renal function.Clin. Pharmacol. Ther. 16:514–519 (1974).
P. J. Perry. Reply.Clin. Pharmacol. Ther. 17:250–251 (1975).
Author information
Authors and Affiliations
Additional information
This work was supported in part by the National Institutes of Health under Grant RR 0704811. The work was also supported in part by U.S. Government Grants MB 00146 and GM 23826, which were made to the Laboratory of Applied Pharmacokinetics at the University of Southern California, School of Medicine.
Rights and permissions
About this article
Cite this article
McAvoy, T.J. Pharmacokinetic modeling of heparin and its clinical implications. Journal of Pharmacokinetics and Biopharmaceutics 7, 331–354 (1979). https://doi.org/10.1007/BF01062533
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01062533