Skip to main content

Thank you for visiting nature.com. 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.

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

Abstract

Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R2=0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R2=0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E . The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 204S–233S.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Chan E, McLachlan AJ, Pegg M, MacKay AD, Cole RB, Rowland M . Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin Pharmacol 1994; 37: 563–569.

    Article  CAS  Google Scholar 

  5. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR . Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 1994; 4: 39–42.

    Article  CAS  Google Scholar 

  6. Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996; 6: 341–349.

    Article  CAS  Google Scholar 

  7. Herman D, Dolzan V, Breskvar K . Genetic polymorphism of cytochrome P450 2C9 and 2C19 in Slovenian population. Zdrav Vest 2003; 72: 347–351.

    Google Scholar 

  8. Lee CR, Goldstein JA, Pieper JA . Cytochrome P450 2C9 polymorphism: a comprehensive review of in vitro and human data. Pharmacogenetics 2002; 12: 251–263.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Furuya H, Fernandez-Salguero P, Gregory W, Taber H, Steward A, Gonzales 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 

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

    Article  CAS  Google Scholar 

  12. Taube J, Halsall D, Baglin T . Influence of cytochrome P450 CYP2C9 polymorphisms on warfarin senstitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816–1819.

    CAS  Google Scholar 

  13. 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 

  14. Freeman BD, Zehnbauer BA, McGrath S, Borecki I, Buchman TG . Cytochrome P450 polymorphisms are associated with reduced warfarin dose. Surgery 2000; 128: 281–285.

    Article  CAS  Google Scholar 

  15. 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 

  16. Higashi M, Veenstra DL, Midori Kondo L, Wittkowsky AK, Srinouanprachanh SL, Farin FM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690–1698.

    Article  CAS  Google Scholar 

  17. Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R . Influence of cytochrome P450 CYP2C9 and 2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance. Clin Pharmacol Ther 2002; 72: 702–710.

    Article  CAS  Google Scholar 

  18. Kamali F, Khan TI, King BP, Frearson R, Kesteven P, Wood P et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther 2004; 75: 204–212.

    Article  CAS  Google Scholar 

  19. http://www.theriaque.org/AnalyseOrdonnances/home.cfm (Date: 16 June 04).

  20. http://www.mhc.com/Cytochromes/ (Date: 16 June 04).

  21. 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 

  22. Takahashi H, Kashima T, Nomizo Y, Muramoto N, Shimizu T, Nasu K et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 1998; 63: 519–528.

    Article  CAS  Google Scholar 

  23. 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 

  24. Bradbury H, Burns E, Stanners A, Travers AF, McAleer SD, Chrystyn H . The clearance of warfarin and its enantiomers in the elderly. Br J Clin Pharmacol 1992; 34: 154P–155P.

    Google Scholar 

  25. Shepherd AM, Hewick DS, Moreland TA, Stevenson IH . Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 4: 315–320.

    Article  CAS  Google Scholar 

  26. Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y . Inhibition selectivity of grapefruit juice components on human cytochromes P450. Arch Biochem Biophys 2000; 378: 356–363.

    Article  CAS  Google Scholar 

  27. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.

    Article  CAS  Google Scholar 

  28. Yasar Ü, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjöqvist F . Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999; 254: 628–631.

    Article  CAS  Google Scholar 

  29. Locatelli I, Kmetec V, Mrhar A, Grabnar I . Determination of warfarin enantiomers and hydroxylated metabolites in human blood plasma by liquid chromatography with achiral and chiral separation. J Chromatogr B 2005; 818: 191–198.

    Article  CAS  Google Scholar 

  30. Breckenridge A, Orme M, Wesseling H, Lewis RJ, Gibbons R . Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol Ther USA 1974; 15: 424–430.

    Article  CAS  Google Scholar 

  31. Takahashi H, Kashima T, Nomoto S, Iwade K, Tainaka H, Shimuz T et al. Comparisons between in vitro and in vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes. Pharmacogenetics 1998; 8: 365–373.

    Article  CAS  Google Scholar 

  32. Hallynck TH, Soep HH, Thomis JA, Boelaert J, Daneels R, Dettli L . Should clearance be normalised to body surface or to lean body mass? Br J Clin Pharmacol 1981; 11: 523–526.

    Article  CAS  Google Scholar 

  33. Sokal RR, Rohlf FJ . Biometry: The Principles and Practice of Statistics in Biological Research, 3rd edn. WH Freeman and Company: New York, 1995 pp 493–499.

    Google Scholar 

Download references

Acknowledgements

We wish to thank Tina Globokar, MD from the University Medical Centre in Ljubljana, and Mitja Lainscak, MD from the General Hospital Murska Sobota for recruiting the patients and providing the clinical data. We also thank Gaj Vidmar, MSc, from the Institute of Biomedical Informatics, Faculty of Medicine in Ljubljana, for his assistance with the statistical analysis of the data. Control DNA samples for CYP2C9 genotyping were kindly provided by Umit Yasar and Marja Liisa Dahl, both formerly from the Karolinska Institutet, Huddinge University Hospital. This work was financially supported by the Ministry of Education, Science and Sport of Slovenia (Grants Nos. PO-0503-0381, P1-0170 and P1-0189-0787)

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V Dolzan.

Additional information

DUALITY OF INTEREST

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herman, D., Locatelli, I., Grabnar, I. et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J 5, 193–202 (2005). https://doi.org/10.1038/sj.tpj.6500308

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500308

Keywords

This article is cited by

Search

Quick links