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Semin Vasc Med 2003; 03(3): 221-230
DOI: 10.1055/s-2003-44457
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Warfarin and Other Coumarin Derivatives: Pharmacokinetics, Pharmacodynamics, and Drug Interactions

Ann K. Wittkowsky
  • University of Washington School of Pharmacy; Anticoagulation Services, University of Washington Medical Center, Seattle WA
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Publication History

Publication Date:
21 November 2003 (online)

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ABSTRACT

Warfarin, a racemic mixture of R- and S-enantiomers, exerts its anticoagulant effect by interfering with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X and proteins C and S. Warfarin displays stereospecific pharmacokinetic and pharmacodynamic properties, and the isomers are differentially metabolized by cytochrome p450 isozymes. Among patients treated with warfarin, there is little correlation among dose, serum concentration, and therapeutic effect, necessitating individualized dosing guided by therapeutic monitoring of the prothrombin time. The pharmacokinetic and pharmacodynamic properties of warfarin as well as its narrow therapeutic index make it particularly susceptible to interactions with other prescription and nonprescription drugs, including dietary supplements. Numerous drug compounds are reported to interact with warfarin, necessitating increased prothrombin time monitoring and warfarin dosing adjustments to maintain safe and effective anticoagulation.

KEYWORDS

Warfarin - pharmacokinetics - pharmacodynamics - drug interactions

REFERENCES

  • 1 Roderick L M. A problem in the coagulation of blood: sweet clover disease of cattle.  Am J Physiol . 1931;  96 413-425
    PubMedGoogle Scholar
  • 2 Campbell H A, Link K P. Studies on the hemorrhagic sweet clover disease IV: the isolation and crystallization of the hemorrhagic agent.  J Biol Chem . 1941;  138 21-33
    PubMedGoogle Scholar
  • 3 Stahman M A, Huebner C F, Link K P. Studies on the hemorrhagic sweet clover disease V: identification and synthesis of the hemorrhagic agent.  J Biol Chem . 1941;  138 513-527
    PubMedGoogle Scholar
  • 4 Link K P. The discovery of dicoumarol and its sequels.  Circulation . 1959;  19 97-107
    CrossrefPubMedGoogle Scholar
  • 5 Majerus P W, Broze G J, Miletich J P, Tollefsen D M. Anticoagulant, thrombolytic, and antiplatelet agents. In: Goodman L, Gilman A, et al., eds. The Pharmacologic Basis of Therapeutics New York: Pergamon Press; 1990
    Google Scholar
  • 6 O'Reilly R A. Studies on the optical enantiomorphs of warfarin in man.  Clin Pharmacol Ther . 1974;  16 348-354
    PubMedGoogle Scholar
  • 7 Thijjsen H HW, Baars L GM, Vervoort H TM. Vitamin 2,3-epoxide reductase: the basis for stereoselectivity of 4-hydroxycoumarin anticoagulant activity.  Br J Pharmacol . 1988;  95 675-682
    PubMedGoogle Scholar
  • 8 Suttie J W. Vitamin K dependent carboxylation of glutamyl residues of proteins.  Biofactors . 1988;  1 55-60
    PubMedGoogle Scholar
  • 9 Whitlon D S, Sadowski J A, Suttie J W. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition.  Biochemistry . 1978;  17 1371-1377
    CrossrefPubMedGoogle Scholar
  • 10 Vermeer C, Hamulyak K. Pathophysiology of vitamin K deficiency and oral anticoagulants.  Thromb Haemost . 1991;  66 153-159
    PubMedGoogle Scholar
  • 11 Fasco M J, Hildebrandt E F, Suttie J W. Evidence that warfarin anticoagulant action involves two distinct reductase activities.  J Biol Chem . 1982;  257 11210-11212
    PubMedGoogle Scholar
  • 12 Malhotra O P, Nesheim M E, Mann K G. The kinetics of activation of normal and gamma-carboxyglutamic acid-deficient prothrombins.  J Biol Chem . 1985;  260 279-287
    PubMedGoogle Scholar
  • 13 Pyoralak K, Jussila J, Mustala O, Siurala M. Absorption of warfarin from stomach and small intestine.  Scand J Gastroenterol . 1971;  6 (suppl 9) 95-103
    PubMedGoogle Scholar
  • 14 Stirling U, Howarth D J, Stockley R. et al . Comparison of the bioavailabilities and anticoagulant activities of two warfarin formulations.  Br J Haematol . 1982;  51 37-45
    PubMedGoogle Scholar
  • 15 O'Reilly R A, Welling P G, Wagner J G. Pharmacokinetics of warfarin following intravenous administration in man.  Thromb Haemost . 1971;  25 178-186
    PubMedGoogle Scholar
  • 16 Hewick D S, McEwen J. Plasma half-lives, plasma metabolites, and anticoagulant efficacies of the enantiomers of warfarin in man.  J Pharm Pharmacol . 1983;  25 458-465
    PubMedGoogle Scholar
  • 17 O'Reilly R. Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin.  J Clin Invest . 1969;  48 193-202
    PubMedGoogle Scholar
  • 18 Chan E, McLachlan A J, Pegg M. et al . Disposition of warfarin enantiomers and metabolism in patients during multiple dosing with racemic warfarin.  Br J Clin Pharmacol . 1994;  37 563-569
    PubMedGoogle Scholar
  • 19 Yacobi A, Udall J A, Levy G. Serum protein binding as a determinant of warfarin body clearance and anticoagulant effect.  Clin Pharmacol Ther . 1976;  19 552-558
    PubMedGoogle Scholar
  • 20 Yacobi A, Stoll R G, DiSanto R, Levy G. Intrasubject variation of warfarin binding in serum of normal subjects.  Res Commun Chem Pathol Pharmacol . 1976;  14 743-746
    PubMedGoogle Scholar
  • 21 Ganeval D, Fischer A M, Barre J. et al . Pharmacokinetics of warfarin in the nephritic syndrome and effect on vitamin K dependent clotting factors.  Clin Nephrol . 1986;  25 75-80
    PubMedGoogle Scholar
  • 22 Routledge P A, Chapman P H, Davies D M, Rawlins M D. Pharmacokinetics and pharmacodynamics of warfarin at steady state.  Br J Pharmacol . 1979;  8 243-247
    PubMedGoogle Scholar
  • 23 Lewis R J, Trager W F. Warfarin metabolism in man: identification of metabolites in urine.  J Clin Invest . 1970;  49 907-913
    PubMedGoogle Scholar
  • 24 Lewis R J, Trager W F, Chan K K. et al . Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone.  J Clin Invest . 1974;  53 1607-1617
    PubMedGoogle Scholar
  • 25 Rettie A E, Korzekwa K R, Kunze K L. et al . Hydroxylation of warfarin by human cDNA-expressed cytochrome p450: a role for p450-2C9 in the etiology of S-warfarin drug interactions.  Chem Res Toxicol . 1992;  5 54-59
    CrossrefPubMedGoogle Scholar
  • 26 Lewis R J, Trager W F, Robinson A J, Chan K K. Warfarin metabolites: the anticoagulant activity and pharmacology of warfarin alcohols.  J Lab Clin Med . 1973;  81 925-931
    PubMedGoogle Scholar
  • 27 Breckenridge A, Orme M, Wesseling H. et al . Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man.  Clin Pharmacol Ther . 1973;  15 424-430
    PubMedGoogle Scholar
  • 28 Wingard L B, O'Reilly R A, Levy G. Pharmacokinetics of warfarin enantiomers: a search for intrasubject correlations.  Clin Pharmacol Ther . 1978;  23 212-217
    PubMedGoogle Scholar
  • 29 Hignite C, Uetriecht J, Tschanz C, Azaroff D. Kinetics of R and S warfarin enantiomers.  Clin Pharmacol Ther . 1980;  28 99-105
    PubMedGoogle Scholar
  • 30 Godbillon J, Richard J, Gerardin A. et al . Pharmacokinetics of the enantiomers of acenocoumarol in man.  Br J Clin Pharmacol . 1981;  12 621-629
    CrossrefPubMedGoogle Scholar
  • 31 Haustein K O. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon.  Semin Thromb Haemost . 1999;  25 5-11
    PubMedGoogle Scholar
  • 32 Choondara I A, Haynes B P, Cholerton S. et al . Enantiomers of warfarin and vitamin K1 metabolism.  Br J Clin Pharmacol . 1986;  22 729-732
    PubMedGoogle Scholar
  • 33 Weiss P, Soff G A, Halkin H, Seligsohn U. Decline of proteins C and S and factors II, VII, IX and X during initiation of warfarin therapy.  Thromb Res . 1987;  45 783-790
    CrossrefPubMedGoogle Scholar
  • 34 Harrison L, Johnston M, Massicotte M P. et al . Comparison of 5mg and 10mg loading doses in initiation of warfarin therapy.  Ann Intern Med . 1997;  126 133-136
    PubMedGoogle Scholar
  • 35 Kumar S, Haight J RM, Tate G. et al . Effect of warfarin on plasma concentrations of vitamin K dependent coagulation factors in patients with stable control and monitored compliance.  Br J Haematol . 1990;  74 82-85
    PubMedGoogle Scholar
  • 36 Hotraphinyo K, Triggs E F, Maybloom B, Maclaine-Cross A. Warfarin sodium: steady state plasma levels and patient age.  Clin Exp Pharmacol Physiol . 1978;  5 143-149
    PubMedGoogle Scholar
  • 37 Routledge P A, Chapman P H, Davies D M, Rawlins M D. Pharmacokinetics and pharmacodynamics of warfarin at steady state.  Br J Clin Pharmacol . 1979;  8 243-247
    PubMedGoogle Scholar
  • 38 Hanston P, Wittkowsky A K. Warfarin drug interactions. In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulant Therapy: Clinical and Operational Guidelines Gaithersburg, MD: Aspen; 1997
    Google Scholar
  • 39 Wells P S, Holbrook A m, Crowther N R, Hirsh J. Interactions of warfarin with drugs and food.  Ann Intern Med . 1994;  121 676-683
    PubMedGoogle Scholar
  • 40 Freedman M D, Olatidoy A G. Clinically significant drug interactions with the oral anticoagulants.  Drug Safety . 1994;  10 381-394
    PubMedGoogle Scholar
  • 41 Testa B, Jenner P. Inhibitors of cytochrome p450s and their mechanism of action.  Drug Metab Rev . 1981;  12 1-117
    PubMedGoogle Scholar
  • 42 Cropp J S, Bussey H I. A review of enzyme induction of warfarin metabolism with recommendations for patient management.  Pharmacotherapy . 1997;  17 719-728
    PubMedGoogle Scholar
  • 43 Wittkowsky A K. Drug interactions update: drugs, herbs, and oral anticoagulation.  J Thromb Thrombolysis . 2001;  12 67-71
    CrossrefPubMedGoogle Scholar
  • 44 Higashi M, Veenstra D L, Wittkowsky A K. et al . Influence of CYP2C9 genetic variants on the risk of overanticoagulation and of bleeding events during warfarin therapy.  JAMA . 2002;  287 690-698
    PubMedGoogle Scholar
  • 45 Rosenbaum M D, Blendon R J, Benson J. et al .Survey of Americans and dietary supplements. National Public Radio/ Henry J. Kaiser Family Foundation/Harvard University Kennedy School of Government; 1999
    Google Scholar
  • 46 Eisenberg D M, Davis R B, Ettner S L. et al . Trends in alternative medicine use in the United States 1990-1997; results of a follow-up national survey.  JAMA . 1998;  280 1569-1575
    CrossrefPubMedGoogle Scholar
  • 47 Kurtzweil P. An FDA Guide to Dietary Supplements. U.S. Food and Drug Administration Publ. No. 99-2323; January 1999
    Google Scholar
  • 48 Bouttata J I, Nace A M. Safety issues with herbal medicinals.  Pharmacotherapy . 2000;  20 257-269
    CrossrefPubMedGoogle Scholar
  • 49 Heck A M, DeWitt B A, Lukes A L. Potential interactions between alternative therapies and warfarin.  Am J Health Syst Pharm . 2000;  57 1221-1227
    PubMedGoogle Scholar
  • 50 Vaes L P, Chyka P A. Interactions of warfarin with garlic, ginger, ginkgo or ginseng: nature of the evidence.  Ann Pharmacother . 2000;  34 1478-1482
    PubMedGoogle Scholar
  • 51 Hoult J R, Paya M. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential.  Gen Pharmacol . 1996;  27 713-722
    CrossrefPubMedGoogle Scholar
  • 52 Newell C A, Anderson L A, Phillipson J D. Herbal Medicinals: A Guide for Health Care Professionals.  London: Pharmaceutical Press; 1996
    Google Scholar