Summary
Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Examples of the former include alteration of the bioavailability of vitamin K by antibiotics, mineral oils or cholestyramine; oestrogens, diuretics and hypolipidaemic agents such as clofibrate may influence vitamin K-dependent clotting factor synthesis, and drugs which affect haemostasis, e.g. via platelet function, will enhance the anticoagulant effect of warfarin.
Pharmacokinetic interactions are better understood. Few drugs have been shown to alter warfarin absorption, the importance of protein binding displacement has been exaggerated, and since warfarin is not eliminated to any extent unchanged by the kidney, the most important kinetic interactions are those due to inhibition or induction of its hepatic metabolism. Isomeric differences in metabolism form an important basis for stereoselective metabolic interactions, especially inhibition; this has been demonstrated with phenylbutazone, metronidazole and co-trimoxazole. Enzyme induction, although recognised for many years, may still pose problems in therapeutics, usually on withdrawal of the inducing agent.
Similar content being viewed by others
References
Aggeler, P.M.; O’Reilly, R.A.; Leong, L. and Kowitz, P.E.: Potentiation of anticoagulant effect of warfarin by phenylbutazone. New England Journal of Medicine 67: 496–501 (1967).
Ambre, J.J. and Fischer, L.J.: Effect of coadministration of aluminium and magnesium hydroxides on absorption of anticoagulants in man. Clinical Pharmacology and Therapeutics 14: 231–237 (1973).
Barker, W.M.; Hermodson, M.N. and Link, K.P.: The metabolism of 4-C14 warfarin sodium by the rat. Journal of Pharmacology and Experimental Therapeutics 171: 307–313 (1970).
Barnes, R.H.; Kwong, E. and Fiala, G.: Effects of the prevention of coprophagy in the rat. Journal of Nutrition 68: 603–614 (1959).
Bjornsson, T.D.; Meffin, P.J.; Swezey, S. and Blaschke, T.F.: Clofibrate displaces warfarin from plasma proteins in man: An example of a pure displacement interaction. Journal of Pharmacology and Experimental Therapeutics 210: 316–321 (1979).
Branch, R.A.; Shand, D.G.; Wilkinson, G.R. and Nies, A.: Increased clearance of antipyrine and propranolol after phenobarbital treatment in the monkey. Relative contributions of enzymic induction and increased hepatic blood flow. Journal of Clinical Investigation 53: 1101–1107 (1974).
Breckenridge, A.M. and Orme, M.L’E: Clinical implications of enzyme induction. Annals of the New York Academy of Sciences 179:421–431 (1971).
Breckenridge, A. and Orme, M.: The plasma half-lives and the pharmacological effect of the enantiomers of warfarin in rats. Life Sciences 11: 337–345 (1972).
Breckenridge, A. and Orme, M.: Kinetics of warfarin absorption in man. Clinical Pharmacology and Therapeutics 14: 955–961 (1973a).
Breckenridge, A. and Orme, M.L’E.: Measurement of plasma warfarin in clinical practice; in Davies and Prichard (Eds) Biological Effects of Drugs in Relation to Their Plasma Concentration, pp. 145–154 (Macmillan Press, London 1973b).
Breckenridge, A.; Orme, M.; Wesseling, H.; Lewis, R.J. and Gibbons, R.: Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clinical Pharmacology and Therapeutics 15: 424–430 (1974).
Brown, C.H.; Natelson, E.A.; Bradshaw, M.W.: Study of the effects of ticarcillin on blood coagulation and platelet function. Antimicrobial Agents and Chemotherapy 7: 652–657 (1975).
Brozović, M.: Oral anticoagulants, vitamin K and prothrombin complex factors. British Journal of Haematology 32: 9–12 (1976).
Christensen, L.K. and Skovsted, L.: Inhibition of drug metabolism by chloramphenicol Lancet 2: 1397–1399 (1969).
Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).
Corn, M.: Effect of phenobarbital and glutethimide on the biological half-life of warfarin. Thrombosis et Diathesis Haemorrhagica 16: 602–612 (1966).
Desmond, P.V.; Patwardhan, R.; Schenker, S. and Speeg, K.V.: Cimetidine impairs the elimination of chlordiazepoxide in humans. Annals of Internal Medicine 93: 266–268 (1980).
Detilleux, M.; Caquet, R. and Laroche, G.: Potentialisation de l’effet des anticoagulants coumariniques par un nouveau diuretique, l’acide tienilique. Nouvelle Presse Medicale 5: 2395 (1976).
Feely, J.; Wilkinson, G.R. and Wood, A.J.J.: Reduction of liver blood flow and propranolol metabolism by cimetidine. New England Journal of Medicine 304: 692–695 (1981).
Gillette, J.R.: Factors affecting drug metabolism. Annals of the New York Academy of Sciences 179: 43–66 (1971).
Grand, A.; Dronin, B. and Arche, G.J.: Potentialisation de l’action anticoagulants des anti-vitamines K par l’acide tienilique. Nouvelle Presse Medicale 6: 2691 (1977).
Hansen, J.M.; Siersboek-Neilson, K. and Skovsted, L.: Carbamazepine-induced acceleration of diphenylhydantoin and warfarin metabolism in man. Clinical Pharmacology and Therapeutics 12: 539–543 (1971a).
Hansen, J.M.; Siersboek-Neilson, K.; Kristensen, M.; Skovsted, L. and Christensen, L.K.: Effect of diphenylhydantoin on the metabolism of dicoumarol in man. Acta Medica Scandinavica 189: 15–19 (1971b).
Hansten, P.D.: Drug Interactions, 4th edition, pp. 33–68 (Lea and Febiger, Philadelphia 1979).
Haworth, E. and Burroughs, A.K.: Disopyramide and warfarin interaction. British Medical Journal 2: 866–867 (1977).
Henry, D.A.; Macdonald, I.A.; Kitchingman, G.; Bell, G.D. and Langman, M.J.S.: Cimetidine and ranitidine: Comparison of effects on hepatic drug metabolism. British Medical Journal 281: 775–777 (1980).
Hetzel, DJ.; Bochner, F.; Hallpike, J.F.; Shearman, D.J.C. and Hann, C.S.: Cimetidine interaction with phenytoin. British Medical Journal 282: 1512 (1981).
Hewick, D.S. and McEwen, J.: Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. Journal of Pharmacy and Pharmacology 25: 458–465 (1973).
Hewick, D.S. and Moreland, T.A.: An NADPH dependent warfarin reductase in human and rat liver and kidney soluble fraction. British Journal of Pharmacology 53: 441P (1975).
Ikeda, M.; Conney, A.H. and Burns, J.J.: Stimulatory effect of phenobarbital and insecticides on warfarin metabolism in the rat. Journal of Pharmacology and Experimental Therapeutics 162: 338–343 (1968).
Jahnchen, E.; Meinertz, T.; Gilfrich, H.J.; Kersting, F. and Groth, U.: Enhanced elimination of warfarin during treatment with cholestyramine. British Journal of Clinical Pharmacology 5: 437–440 (1978).
Jain, A.; McMahon, G.F.; Slattery, J.T. and Levy, G.: Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin. Clinical Pharmacology and Therapeutics 25: 61–66 (1979).
Kater, R.M.H.; Tobon, F. and Iber, F.L.: Increased rate of tolbutamide metabolism in alcoholic patients. Journal of the American Medical Association 207: 363–365 (1969).
Kelly, J.G. and O’Malley, K.O.: Clinical pharmacokinetics of oral anticoagulants. Clinical Pharmacokinetics 4: 1–15 (1979).
Klotz, U. and Reimann, I.: Delayed clearance of diazepam due to cimetidine. New England Journal of Medicine 302: 1012–1014 (1980).
Koch-Weser, J. and Sellers, E.M.: Drug interactions with coumarin anticoagulants. New England Journal of Medicine 285: 487–498, 547–558 (1971).
Lewis, R.J. and Trager, W.F.: Warfarin metabolism in man: Identification of metabolites in urine. Journal of Clinical Investigation 49: 907–913 (1970).
Lewis, R.J. and Trager, W.F.: The metabolic fate of warfarin: Studies on the metabolites in plasma. Annals of the New York Academy of Science 179: 205–212 (1971).
Lewis, R.J.; Trager, W.F.; Chan, K.K.; Breckenridge, A.; Orme, M.; Rowland, M. and Scnary, W.: Warfarin: Stereochemical aspects of its metabolism and the interaction with phenylbutazone. Journal of Clinical Investigation 53: 1607–1617 (1974).
MacLeod, S.M. and Sellers, E.M.: Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants. Drugs 11:461–470 (1976).
Magid, E.: Tolerance to anticoagulants during antibiotic therapy. Scandinavian Journal of Clinical and Laboratory Investigation 14: 565–566 (1962).
Martinowitz, U.; Rabinovici, J.; Goldfarb, D.; Many, A. and Bank, H.: Interaction between warfarin sodium and amiodarone. New England Journal of Medicine 304: 671–672 (1981).
Meinertz, T.; Gilfrich, HJ.; Groth, U.; Jonen, H.G. and Jahnchen, E.: Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine. Clinical Pharmacology and Therapeutics 21: 731–735 (1977).
Musa, M.N. and Lyons, L.L.: Absorption and disposition of warfarin: Effects of food and liquids. Current Therapeutic Research 20: 630–633 (1976).
Nenci, G.G.; Agnelli, G. and Berretini, M.: Biphasic sulphin-pyr-azone-warfarin interaction. British Medical Journal 282: 1361–1362 (1981).
Ohnhaus, E.E. and Park, B.K.: Measurement of urinary 6-β-hy-droxycortisol excretion as an in vivo parameter in the clinical assessment of the microsomal enzyme-inducing capacity of antipyrine, phenobarbitone and rifampicin. European Journal of Clinical Pharmacology 15: 139–145 (1979).
O’Reilly, R.A.: Interaction of sodium warfarin and rifampicin. Annals of Internal Medicine 81: 337–340 (1974).
O’Reilly, R.A.: The stereoselective interaction of warfarin and metronidazole in man. New England Journal of Medicine 295: 354–357 (1976).
O’Reilly, R.A.: Lack of effect of mealtime wine on the hypoprothrombinaemia of oral anticoagulants. American Journal of Medical Sciences 277: 189–194 (1979).
O’Reilly, R.A.: Spironolactone and warfarin interaction. Clinical Pharmacology and Therapeutics 27: 198–201 (1980a).
O’Reilly, R.A.: Stereoselective interaction of trimethoprim-sul-famethoxazole with the separated enantiomorphs of racemic warfarin in man. New England Journal of Medicine 302: 33–35 (1980b).
O’Reilly, R.A. and Aggeler, P.M.: Determinants of the response to oral anticoagulant drugs in man. Pharmacological Reviews 22: 35–96 (1970).
O’Reilly, R.A.; Aggeler, P.M.; Hogg, M.S. and Leong, L.S.: Studies on the coumarin anticoagulant drugs: Assay of warfarin and its biological application. Thrombosis et Diathesis Haemorrhagica 8: 82–95 (1962).
O’Reilly, R.A.; Aggeler, P.M. and Leong, L.S.: Studies on the coumarin anticoagulant drugs: The pharmacodynamics of warfarin in man. Journal of Clinical Investigation 42: 1542–1551 (1963).
O’Reilly, R.A.; Sahud, M.A. and Robinson, A.J.: Studies on the interaction of warfarin and clofibrate in man. Thrombosis et Diathesis Haemorrhagica 27: 309–318 (1972).
O’Reilly, R.A.; Trager, W.F.; Motley, E.H. and Howald, W.: Stereoselective interaction of phenylbutazone with (I2C/I3C) warfarin pseudoracemates in man. Journal of Clinical Investigation 65: 746–753 (1980).
O’Reilly, R.A.; Welling, P.G. and Wagner, J.G.: Pharmacokinetics of warfarin following intravenous administration to man. Thrombosis et Diathesis Haemorrhagica 25: 178–186 (1971).
Orme, M.; Breckenridge, A. and Brooks, R.V.: Interactions of benzodiazepines with warfarin. British Medical Journal 3: 611–614 (1972).
Park, B.K. and Leck, J.B.: On the mechanism of salicylateinduced hypoprothrombinaemia. Journal of Pharmacy and Pharmacology 33: 25–28 (1980).
Parke, D.V.: In Parke (Ed.) Enzyme Induction, pp. 207–272 (Plenum Press, London and New York 1975).
Penner, J.A. and Abbrecht, P.H.: Lack of interaction between ibuprofen and warfarin. Current Therapeutic Research 18: 862–871 (1975).
Peters, M.A. and Fouts, J.R.: The inhibitory effect of aureomycin (chlortetracycline) pretreatment on some rat liver microsomal enzyme activities. Biochemical Pharmacology 18: 1511–1517 (1969).
Pond, S.M.; Graham, G.G.; Wade, D.N. and Sudlow, G.: The effects of allopurinol and clofibrate on the elimination of coumarin anticoagulants in man. Australian and New Zealand Journal of Medicine 5: 324–328 (1975).
Quick, A.J. and Clesceri, L.: Influence of acetylsalicylic acid and salicylamide on the coagulation of blood. Journal of Pharmacology and Experimental Therapeutics 128: 95–98 (1960).
Rees, A.; Dalai, J.J.; Reid, P.G.; Henderson, A.H. and Lewis, M.J.: Dangers of amiodarone and anticoagulant treatment. British Medical Journal 282: 1756–1757 (1981).
Reimann, I.W.; Klotz, U.; Siems, B. and Frolich, J.C.: Cimetidine increases steady state plasma levels of propranolol. British Journal of Clinical Pharmacology 12: 785–790 (1981).
Robinson, D.S.; Benjamin, D.M. and McCormack, J.J.: Interaction of warfarin and non-systemic gastrointestinal drugs. Clinical Pharmacology and Therapeutics 12: 491–495 (1971).
Roth, G.J. and Majerus, P.W.: The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. Journal of Clinical Investigation 56: 624–632 (1975).
Roth, G.J.; Stanford, N. and Majerus, P.W.: Acetylation of prostaglandin synthetase by aspirin. Proceedings of the National Academy of Science, USA 72: 3073–3076 (1975).
Schrogie, J.J.; Solomon, H.M. and Zieve, P.D.: Effect of oral contraceptives on vitamin K-dependent clotting activity. Clinical Pharmacology and Therapeutics 8: 670–675 (1967).
Sellers, E.M. and Koch-Weser, J.: Displacement of warfarin from human albumin by diazoxide and ethacrynic, mefenamic and naladixic acids. Clinical Pharmacology and Therapeutics 11: 524–529 (1970).
Serlin, M.J.: MD Thesis, University of Birmingham (1980).
Serlin, M.J.; Mossman, S.; Sibeon, R.G.; Breckenridge, A.M.; Williams, J.R.B.; Atwood, J.C. and Willoughby, J.M.T.: Cimetidine: Interaction with oral anticoagulants in man. Lancet 2:317–319 (1979).
Serlin, M.J.; Mossman, S.; Sibeon, R.G.; Tempero, K. and Breckenridge, A.M.: Interaction between diflunisal and warfarin. Clinical Pharmacology and Therapeutics 28: 493–498 (1980).
Serlin, M.J.; Sibeon, R.G. and Breckenridge, A.M.: Lack of effect of ranitidine on warfarin action. British Journal of Clinical Pharmacology 12: 791–794 (1981a).
Serlin, M.J.; Sibeon, R.G. and Green, G.J.: Dangers of amiodarone and anticoagulant treatment. British Medical Journal 283: 58 (1981b).
Suttie, J.W.; Grant, G.A.; Esmon, C.T. and Shah, D.V.: Postribosomal function of vitamin K1 in prothrombin synthesis. Mayo Clinic Proceedings 49: 933–940 (1974).
Udall, J.A.: Human sources and absorption of vitamin K in relation to anticoagulation stability. Journal of the American Medical Association 194: 127–129 (1965).
Vesell, E.S.; Passananti, T. and Greene, F.E.: Genetic control of drug levels and the induction of drug metabolism enzymes in man: Individual variability in the extent of allopurinal and nortriptylline inhibition of drug metabolism. Annals of the New York Academy of Sciences 179: 752–773 (1971).
Vesell, E.S.; Passananti, G.T. and Johnson, A.O.: Failure of indomethacin and warfarin to interact in normal human volunteers. Journal of Clinical Pharmacology 15: 486–495 (1975).
Vesell, E.S. and Shively, C.A.: Liquid Chromatographic assay of warfarin: Similarity of warfarin half-lives in human subjects. Science 184: 466–468 (1974).
Wilkinson, C.F.; Hetnarski, K. and Hicks, L.J.: Substituted imidazoles as inhibitors of microsomal oxidation and insecticide synergists. Pesticide Biochemistry and Physiology 4: 299–312 (1974).
Yacobi, A. and Levy, G.: Pharmacokinetics of the warfarin enantiomers in rats. Journal of Pharmacokinetics and Biopharmaceutics 2: 239–255 (1974).
Yacobi, A.; Stoll, R.G.; Di Santo, A.R. and Levy, G.: Intersubject variation of warfarin binding to protein in serum of normal subjects. Research Communications in Chemical Pathology and Pharmacology 14: 743–746 (1976).
Yates, M.S.; Hiley, C.R.; Roberts, P.J.; Back, D.J. and Crawford, F.E.: Differential effects of hepatic microsomal enzyme inducing agents on liver blood flow. Biochemical Pharmacology 27: 2617–2621 (1978).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Serlin, M.J., Breckenridge, A.M. Drug Interactions with Warfarin. Drugs 25, 610–620 (1983). https://doi.org/10.2165/00003495-198325060-00004
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-198325060-00004