Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors


The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1



adenosine triphosphate-binding cassette




cytochrome P450


deoxynucleotide triphospate


generalised linear models procedure in SAS

LS means:

least-squares means


multidrug resistance




prothrombin time international normalised ratio


  1. Hardman JG, Limbird LE, Goodman Gilman A (eds). Goodman and Gilman's. The Pharmacological Basis of Therapeutics, 10th edn McGraw-Hill Professional: New York 2001.

    Google Scholar 

  2. Linder MW . Gentic mechanisms for hypersensitivity and resistance to the anticoagulant warfarin. Clin Chim Acta 2001; 308: 9–15.

    Article  CAS  Google Scholar 

  3. Penning van Beest FJA, van Meegen E, Rosendaal FR, Stricker BHC . Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Haemost 2001; 86: 569–574.

    Article  CAS  Google Scholar 

  4. Horton JD, Bushwick BM . Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999; 3: 635–646.

    Google Scholar 

  5. Landefeld CS, Beyth RJ . Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315–328.

    Article  CAS  Google Scholar 

  6. Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1998; 114: 445S–469S.

    Article  CAS  Google Scholar 

  7. Takahashi H, Echizen H . Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J 2003; 3: 202–214.

    Article  CAS  Google Scholar 

  8. Lubetsky A, Dekel-Stern E, Chetrit A, Lubin F, Halkin H . Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999; 81: 396–399.

    Article  CAS  Google Scholar 

  9. Wells PS, Holbrook AM, Crowther NR, Hirsh J . Interactions of warfarin with drugs and food. Ann Intern Med 1994; 121: 676–683.

    Article  CAS  Google Scholar 

  10. Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH . The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124: 970–979.

    Article  CAS  Google Scholar 

  11. Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A et al. Interindividual variability in sensitivity to warfarin—nature or nurture? Clin Pharmacol Ther 2001; 70: 159–164.

    Article  CAS  Google Scholar 

  12. Harder S, Thurmann P . Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet 1996; 30: 416–444.

    Article  CAS  Google Scholar 

  13. Kaminsky LS, Zhang Z . Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73: 67–74.

    Article  CAS  Google Scholar 

  14. Daly AK, King BP . Pharmacogenetics of oral anticoagulants. Pharmacogenetics 2003; 13: 247–252.

    Article  CAS  Google Scholar 

  15. Aithal GP, Day CP, Kesteven PJ, Daly AK . Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717–719.

    Article  CAS  Google Scholar 

  16. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. J Am Med Assoc 2002; 287: 1690–1698.

    Article  CAS  Google Scholar 

  17. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM et al. The role of the CYP2C9-Leu 359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996; 6: 341–349.

    Article  CAS  Google Scholar 

  18. Furuya H, Fernandez Salguero P, Gregory W, Taber H, Steward A, Gonzalez FJ et al. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995; 5: 389–392.

    Article  CAS  Google Scholar 

  19. Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997; 7: 361–367.

    Article  CAS  Google Scholar 

  20. Ogg MS, Brennan P, Meade T, Humphries SE . CYP2C9*3 allelic variant and bleeding complications [Comment]. Lancet 1999; 354: 1124.

    Article  CAS  Google Scholar 

  21. Taube J, Halsall D, Baglin T . Influence of cytochrome P-450CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816–1819.

    CAS  Google Scholar 

  22. Margaglione M, Colaizzo D, D'Andrea G, Brancaccio V, Ciampa A, Grandone E et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775–778.

    Article  CAS  Google Scholar 

  23. Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD . The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 2002; 194: 267–273.

    Article  Google Scholar 

  24. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R . Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002; 72: 702–710.

    Article  CAS  Google Scholar 

  25. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J et al. Sequence diversity in CYP 3A promoters and characterization of the genetic basis of polymorphic CYP 3A5 expression. Nat Genet 2001; 27: 383–391.

    Article  CAS  Google Scholar 

  26. Westlind-Johnsson A, Malmebo S, Johansson A, Otter C, Andersson TB, Johansson I et al. Comparative analysis of CYP3A expression in human liver suggests only a minor role for CYP3A5 in drug metabolism. Drug Metab Dispos 2003; 31: 755–761.

    Article  CAS  Google Scholar 

  27. Sussman NL, Waltershied M, Butler T, Cali JJ, Riss T, Kelly JH . The predictive nature of high throughput toxicity screening using a human hepatocyte cell line. Cell Notes 2002; 3: 7–10,

    Google Scholar 

  28. Brinkmann U, Eichelbaum M . Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J 2001; 1: 59–64.

    Article  CAS  Google Scholar 

  29. Wandel C, Kim RB, Kajiji S, Guengerich P, Wilkinson GR, Wood AJ . P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. Cancer Res 1999; 59: 3944–3948.

    CAS  PubMed  Google Scholar 

  30. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–3478.

    Article  CAS  Google Scholar 

  31. Taghavi A, Jonson T, Stockelberg D . Survey of complications following treatment with anticoagulants. A computerized search for hemorrhagic complications completes manual reporting. Läkartidningen 1999; 96: 3421–3424.

    CAS  PubMed  Google Scholar 

  32. Levine MN, Raskob G, Landefeld S, Kearon C . Hemorrhagic complications of anticoagulant treatment. Chest 1998; 114: 511S–523S.

    Article  CAS  Google Scholar 

  33. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-450 in the etiology of (S)-warfarin–drug interactions. Chem Res Toxicol 1992; 5: 54–59.

    Article  CAS  Google Scholar 

  34. Siddiqui A, Kerb R, Wheale ME, Brinkmann U, Smith A, Goldstein DB et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med 2003; 348: 1442–1448.

    Article  CAS  Google Scholar 

  35. Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001; 70: 189–199.

    Article  CAS  Google Scholar 

  36. Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol 2002; 53: 526–534.

    Article  CAS  Google Scholar 

  37. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003; 13: 481–494.

    Article  CAS  Google Scholar 

  38. Iqbal O, Aziz S, Hoppensteadt DA, Ahmad S, Walenga JM, Bakhos M et al. Emerging anticoagulant and thrombolytic drugs. Exp Opin Emerg Drugs 2001; 6: 111–135.

    CAS  Google Scholar 

  39. Sjöblom L, Hårdemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32: 2567–2574.

    Article  Google Scholar 

  40. Syvänen AC . Solid phase mini-sequencing. In: Taylor GR (ed). Laboratory Methods for the Detection of Mutations and Polymorphism. CRC Press: Boca Raton, FL 1997: 53–64.

    Google Scholar 

  41. Ronaghi M, Uhlén M, Nyrén P . A sequencing method based on real-time pyrophosphate. Science 1998; 281: 363–365.

    Article  CAS  Google Scholar 

  42. Lindblad-Toh K, Winchester E, Daly MJ, Wang DG, Hirschhorn JN, Laviolette JP et al. Large scale discovery and genotyping of single-nucleotide polymorphisms in the mouse. Nat Genet 2000; 24: 381–386.

    Article  CAS  Google Scholar 

  43. Makridakis NM, Reichardt JK . Multiplex automated primer extension analysis: simultaneous genotyping of several polymorphisms. Biotechniques 2001; 31: 1374–1380.

    Article  CAS  Google Scholar 

  44. Stephens M, Smith NJ, Donnelly P . A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 2001; 68: 978–989.

    Article  CAS  Google Scholar 

Download references


We thank all participating patients, nurses and doctors, especially RN Ulla Prosén and RN Marine Sundin. We are indebted to Drs Hans-Göran Hårdemark and Anders Carlsson for helping to hunt down the cases. Dr Pär Hallberg is thanked for interesting ideas and discussions. BSc Gunilla Frenne, Dr Sherwan Zindrou and Mr Lars Söderlund have given invaluable technical assistance. Pyrosequencing AB provided reagents for CYP3A5 genotyping. Ms Kristi Kuljus has provided statistical expertise. The Swedish Foundation for Strategic Research, the Federation of County Councils, the Tore Nilson Foundation for Medical Research, the Royal Scientific Society's Research Foundation to the memory of Margit Bäxell, and the foundations Gustaf Adolf Johansson and Mary, Åke and Hans Ländell and the clinical research support (ALF) at Uppsala University funded this study.

Author information

Authors and Affiliations


Corresponding author

Correspondence to M Wadelius.

Additional information


None declared.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wadelius, M., Sörlin, K., Wallerman, O. et al. Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 4, 40–48 (2004).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • warfarin
  • bleeding
  • CYP2C9
  • CYP3A5
  • ABCB1
  • MDR1

This article is cited by


Quick links