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

Ann K. Wittkowsky

doi:10.1055/s-2003-44457

Seminars in Vascular Medicine, Table of Contents

Semin Vasc Med 2003; 03(3): 221-230
DOI: 10.1055/s-2003-44457

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

Abstract

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

Full Text

References

REFERENCES

1 Roderick L M. A problem in the coagulation of blood: sweet clover disease of cattle. Am J Physiol . 1931; 96 413-425
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
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
4 Link K P. The discovery of dicoumarol and its sequels. Circulation . 1959; 19 97-107
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
6 O'Reilly R A. Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther . 1974; 16 348-354
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
8 Suttie J W. Vitamin K dependent carboxylation of glutamyl residues of proteins. Biofactors . 1988; 1 55-60
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
10 Vermeer C, Hamulyak K. Pathophysiology of vitamin K deficiency and oral anticoagulants. Thromb Haemost . 1991; 66 153-159
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
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
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
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
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
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
17 O'Reilly R. Interaction of the anticoagulant drug warfarin and its metabolites with human plasma albumin. J Clin Invest . 1969; 48 193-202
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
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
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
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
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
23 Lewis R J, Trager W F. Warfarin metabolism in man: identification of metabolites in urine. J Clin Invest . 1970; 49 907-913
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
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
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
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
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
29 Hignite C, Uetriecht J, Tschanz C, Azaroff D. Kinetics of R and S warfarin enantiomers. Clin Pharmacol Ther . 1980; 28 99-105
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
31 Haustein K O. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon. Semin Thromb Haemost . 1999; 25 5-11
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
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
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
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
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
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
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
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
40 Freedman M D, Olatidoy A G. Clinically significant drug interactions with the oral anticoagulants. Drug Safety . 1994; 10 381-394
41 Testa B, Jenner P. Inhibitors of cytochrome p450s and their mechanism of action. Drug Metab Rev . 1981; 12 1-117
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
43 Wittkowsky A K. Drug interactions update: drugs, herbs, and oral anticoagulation. J Thromb Thrombolysis . 2001; 12 67-71
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
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
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
47 Kurtzweil P. An FDA Guide to Dietary Supplements. U.S. Food and Drug Administration Publ. No. 99-2323; January 1999
48 Bouttata J I, Nace A M. Safety issues with herbal medicinals. Pharmacotherapy . 2000; 20 257-269
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
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
51 Hoult J R, Paya M. Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen Pharmacol . 1996; 27 713-722
52 Newell C A, Anderson L A, Phillipson J D. Herbal Medicinals: A Guide for Health Care Professionals. London: Pharmaceutical Press; 1996