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.

  • Clinical Implications
  • Published:

Clinical Implication

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

The Pharmacogenomics Journal volume 3, pages 202–214 (2003)Cite this article

A large (>10-fold) interindividual variation in the dose requirement of warfarin to achieve optimal therapeutic anticoagulation responses has often posed difficulties for clinicians to individualize warfarin doses to their patients. In addition, therapeutic targets measured by international normalized ratio (INR) of prothrombin time appear to differ between populations: INR of 2–3 for most indications in Caucasian patients1 and 1.5–2.5 for Asian patients.2,3 In this context, there is a strong demand to clarify concealed factors associated with a substantial interindividual variability of anticoagulation responses to warfarin. It is widely recognized that pharmacokinetic and pharmacodynamic factors contribute to the intra- and interindividual variabilities in the dosage requirement of warfarin. Clinically available warfarin is a racemic mixture of (R)- and (S)-warfarin and the anticoagulation effect of (S)-warfarin is three to five times more potent than (R)-warfarin.4 Therefore, the interindividual variability in the disposition of (S)-warfarin would be the most important pharmacokinetic parameter associated with variable anticoagulation responses to warfarin. (S)-warfarin is metabolized almost exclusively by CYP2C9 to its major metabolite, (S)-7-hydroxywarfarin in humans.5 According to the physiological model,6 the steady-state unbound plasma concentrations (Cu) of an orally administered drug being eliminated mainly by hepatic metabolism depend solely on the hepatic intrinsic clearance (CLint,h) for the drug. This pharmacokinetic parameter represents the hepatic enzyme activity involved in the metabolism of the drug. Collectively, the hepatic CYP2C9 activity would be one of the most critical determinants of the interindividual variability in the anticoagulation response to warfarin.

Genetic polymorphisms of CYP2C9 have been extensively studied in the connection with the alterations in enzyme activity. Among the 11 variant alleles of CYP2C9 so far reported,7 CYP2C9*2 and CYP2C9*3 would be most important in the light of their influence on in vitro and in vivo metabolic activities and allelic frequencies in different ethnic populations.8,9,10,11,12,13,14,15 CYP2C9*416 has been detected so far in only one Japanese patient whose phenytoin clearance was shown to be substantially reduced as compared with those possessing CYP2C9*1/*1. The allelic frequency of this variant should be very low in Japanese and no information is available in Caucasian and African-American populations. CYP2C9*5 was detected in five of 110 African-American17 and three of 183 Tanzanians,18 but none in Caucasian or Asians. Although no information is available for the in vivo enzyme activity of CYP2C9*5 at present, recombinant proteins of CYP2C9*5 and CYP2C9*4 exhibited markedly reduced enzyme activities as compared with that of the wild-type CYP2C9 in vitro.17,19 While the allelic frequency of CYP2C9*6,20 a null allele of CYP2C9, has been shown to be 0.6% in African-American, none of the Caucasians or Asians have been shown to possess this variant allele. The finding that a homozygote of CYP2C9*6 developed severe phenytoin toxicity by an oral phenytoin dosing of 300 mg/day indicates that this allele would be associated with a substantially reduced in vivo enzyme activity. Among the six other newly discovered CYP2C9 variant alleles (ie, from CYP2C9*7 to CYP2C9*12),21 CYP2C9*11 (R335W) showed markedly defective metabolic activity in in vitro systems. Nonetheless, there is a paucity of information regarding the in vivo activities of these variants. Recently, different groups of investigators have reported the relation between CYP2C9 polymorphisms (ie, CYP2C9*2 and CYP2C9*3) and the daily dose requirement of warfarin and risks of bleeding complications during anticoagulation therapy.22,23,24,25,26,27,28,29,30,31,32 These studies support an idea that the genetic polymorphisms of CYP2C9 would contribute to the interindividual variability of the anticoagulation responses to warfarin along with the previously known clinical and environmental variables (eg, age, concomitantly administered drugs, foods and clinical indications).33,34

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. 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 

  2. Yamaguchi T . Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Stroke 2000; 31: 817–821.

    Article  CAS  Google Scholar 

  3. Matsuyama K, Matsumoto M, Sugita T, Nishizawa J, Yoshida K, Tokuda Y et al. Anticoagulant therapy in Japanese patients with mechanical mitral valves. Circ J 2002; 66: 668–670.

    Article  CAS  Google Scholar 

  4. O’Reilly RA . Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther 1974; 16: 348–354.

    Article  Google Scholar 

  5. 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-4502C9 in the etiology of (S)-warfarin–drug interactions. Chem Res Toxicol 1992; 5: 54–59.

    Article  CAS  Google Scholar 

  6. Wilkinson GR, Shand DG . A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18: 377–390.

    Article  CAS  Google Scholar 

  7. Oscarson M, Ingelman-Sunberg M, Daly AK Nebert DW, Brockmöller J, Eichelbaum M et al. Human cytochrome P450 (CYP) allele nomenclature committee (web site), 2002; http://www.imm.ki.se/CYPalleles/.

  8. Takahashi H, Echizen H . Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40: 587–603.

    Article  CAS  Google Scholar 

  9. Lee CR, Goldstein JA, Pieper JA . Cytochrome P450 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12: 251–263.

    Article  CAS  Google Scholar 

  10. 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 

  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. 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 

  13. Takahashi H, Kashima T, Nomoto S, Iwade K, Tainaka H, Shimizu 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 

  14. Takahashi H, Wilkinson GR, Caraco Y, Muszkat M, Kim RB, Kashima T et al. Population differences in (S)-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese. Clin Pharmacol Ther 2003; 73: 253–263.

    Article  CAS  Google Scholar 

  15. 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 

  16. Imai J, Ieiri I, Mamiya K, Miyahara S, Furuumi H, Nanba E . Polymorphism of the cytochrome P450(CYP)2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics 2000; 10: 85–89.

    Article  CAS  Google Scholar 

  17. Dickmann LJ, Rettie AE, Kneller MB, Kim RB, Wood AJJ, Stein MC et al. Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 2001; 60: 382–387.

    Article  CAS  Google Scholar 

  18. Yasar Ü, Aklillu E, Canaparo R, Sandberg M, Sayi J, Roh HK et al. Analysis of CYP2C9*5 in Caucasian, Oriental and Black-African populations. Eur J Clin Pharmacol 2002; 58: 555–558.

    Article  CAS  Google Scholar 

  19. Ieiri I, Tainaka H, Morita T, Hadama A, Mamiya K, Hayashibara M et al. Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis. Ther Drug Monit 2000; 22: 237–244.

    Article  CAS  Google Scholar 

  20. Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA . Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 2001; 11: 803–808.

    Article  CAS  Google Scholar 

  21. Goldstein JA . Polymorphisms in the human CYP2C subfamily. Drug Metab Rev 2002; 34 (Suppl 1): 5 (Abstract).

    Google Scholar 

  22. 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 

  23. Aithal GP, Day CP, Kesteven PJL, 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 

  24. Aithal GP, Day CP, Kesteven PJL, Daly AK . Warfarin dose requirement and CYP2C9 polymorphisms—authors’ reply. Lancet 1999; 353: 1972–1973.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. 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 

  28. 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 

  29. Tabrizi AR, McGrath SD, Blinder MA, Buchman TG, Zehnbauer BA, Freeman BD . Extreme warfarin sensitivity in siblings associated with multiple cytochrome P450 polymorphisms. Am J Hematol 2001; 67: 144–146.

    Article  CAS  Google Scholar 

  30. 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 

  31. 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. JAMA 2002; 287: 1690–1698.

    Article  CAS  Google Scholar 

  32. Leung AYH, Chow HCH, Kwong YL, Lie AKW, Fung ATK, Chow WH et al. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood 2001; 98: 2584–2587.

    Article  CAS  Google Scholar 

  33. James AH, Britt RP, Raskino CL, Thompson SG . Factors affecting the maintenance dose of warfarin. J Clin Pathol 1992; 45: 704–706.

    Article  CAS  Google Scholar 

  34. 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 

  35. O’Reilly RA . The second reported kindred with hereditary resistance to oral anticoagulant drugs. N Engl J Med 1970; 282: 1448–1451.

    Article  Google Scholar 

  36. Cain D, Hutson SM, Wallin R . Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in rat liver. Thromb Hemost 1998; 80: 128–133.

    Article  CAS  Google Scholar 

  37. Kohn MH, Pelz H-J . A gene-anchored map position of the rat warfarin-resistance locus, Rw, and its orthologs in mice and humans. Blood 2000; 96: 1996–1998.

    CAS  PubMed  Google Scholar 

  38. Wallin R, Hutson SM, Cain D, Sweatt A, Sane DC . A molecular mechanism for genetic warfarin resistance in the rat. FASEB J 2001; 15: 2542–2544.

    Article  CAS  Google Scholar 

  39. Seligsohn U, Lubetsky A . Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222–1231.

    Article  CAS  Google Scholar 

  40. Mannucci PM . Genetic control of anticoagulation. Lancet 1999; 353: 688–689.

    Article  CAS  Google Scholar 

  41. Oldenburg J, Quenzel EM, Harbrecht U, Fregin A, Kress W, Müller CR et al. Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 1997; 98: 240–244.

    Article  CAS  Google Scholar 

  42. Crespi CL, Miller VP . The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 7: 203–210.

    Article  CAS  Google Scholar 

  43. Stubbins MJ, Harries LW, Smith G, Tarbit MH, Roland Wolf C . Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 6: 429–439.

    Article  CAS  Google Scholar 

  44. 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 

  45. Takahashi H, Ishikawa S, Nomoto S, Nishigaki Y, Ando F, Kashima T et al. Developmental changes in pharmacokinetics and pharmacodynamics of warfarin enantiomers in Japanese children. Clin Pharmacol Ther 2000; 68: 541–555.

    Article  CAS  Google Scholar 

  46. Takahashi H, Kashima T, Kimura S, Murata N, Takaba T, Iwade K et al. Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome: application of in vitro approaches to predicting in vivo reduction of (S)-warfarin clearance. Drug Metab Dispos 1999; 27: 1179–1186.

    CAS  PubMed  Google Scholar 

  47. Porter RS, Sawyer WT . Warfarin. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 3rd edn. Applied Therapeutics Inc: Vancouver, 1992, pp 31(1)–(46).

    Google Scholar 

  48. Rose VL, Kwaan HC, Williamson K, Hoppensteadt D, Walenga J, Fareed J . Protein C antigen deficiency and warfarin necrosis. Am J Clin Pathol 1986; 86: 653–655.

    Article  CAS  Google Scholar 

  49. Takahashi H, Sato T, Shimoyama Y, Shioda N, Shimizu T, Kubo S et al. Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone. Clin Pharmacol Ther 1999; 66: 569–581.

    Article  CAS  Google Scholar 

  50. Feinberg WM, Cornell ES, Nightingale SD, Pearce LA, Tracy RP, Hart RG et al. Relationship between prothrombin activation fragment F1.2 and international normalized ratio in patients with atrial fibrillation. Stroke 1997; 28: 1101–1106.

    Article  CAS  Google Scholar 

  51. Wynne H, Cope L, Kelly P, Whittingham T, Edwards C, Kamali F . The influence of age, liver size and enantiomer concentrations on warfarin requirements. Br J Clin Pharmacol 1995; 40: 203–207.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Abernethy DR, Kaminsky LS, Dickinson TH . Selective inhibition of warfarin metabolism by diltiazem in humans. J Pharmacol Exp Ther 1991; 257: 411–415.

    CAS  PubMed  Google Scholar 

  53. 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 

Download references

Acknowledgements

This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (12670703) and the Japanese Research foundation for Clinical Pharmacology.

Author information

Authors and Affiliations

  1. Department of Pharmacotherapy, Meiji Pharmaceutical University, Tokyo, Japan

    H Takahashi & H Echizen

Authors
  1. H Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Echizen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Takahashi.

Additional information

DUALITY OF INTEREST

None.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takahashi, H., Echizen, H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J 3, 202–214 (2003). https://doi.org/10.1038/sj.tpj.6500182

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500182

This article is cited by

Search

Advanced search

Quick links