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European Journal of Clinical Pharmacology

, Volume 58, Issue 11, pp 739–745 | Cite as

Genetic and environmental risk factors for oral anticoagulant overdose

  • C. Verstuyft
  • A. Robert
  • S. Morin
  • M. A. Loriot
  • A. Flahault
  • P. Beaune
  • C. Funck-Brentano
  • P. Jaillon
  • L. Becquemont
Pharmacokinetics and Disposition

Abstract

Background

Cytochrome P 450 2C9 (CYP2C9) allelic variant carriers have been shown to experience hyper-responsiveness to small doses of oral anticoagulants (OAs) (warfarin or acenocoumarol) and a higher bleeding rate.

Objectives

To determine the relative frequencies of different risk factors for OA overdose including diet, concomitant diseases, drug interactions, recent increment of OA dose and CYP2C9 genetic polymorphism among hospitalised patients.

Materials and methods

Frequencies of the different risk factors for OA overdose were determined in a prospective case-control study. Seventy-five consecutive patients with an International normalised ratio (INR) greater than 4 were matched with seventy-five control patients with an INR greater than 2 but less than 3.5 with respect to age, prescribed OA and daily dose. Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was detected by the TaqMan allelic discrimination assay.

Results

Drug interactions and a recent increment of OA dose were the only significant independent risk factors identified in the first analysis with odds ratio 2.13 (95% CI: 1.06–4.28) and 3.38 (95%CI: 1.51–7.57), respectively. A recent increment of OA dose was the only significant independent risk factor identified among the patients treated with coumarin derivatives (acenocoumarol or warfarin), excluding those treated with fluindione; the odds ratio was 4.3 (95% CI: 1.5–12.3). CYP2C9 genetic polymorphism did not significantly predict the increased risk of OA overanticoagulation in this study. However three homozygous CYP2C9*3/CYP2C9*3 genotype patients were found among the cases, whereas no such patients could be identified among controls.

Conclusion

This is the first observational study investigating the role of CYP2C9 genetic polymorphism together with other environmental OA overdose risk factors. Our results support the view that although the CYP2C9*3/CYP2C9*3 genotype is associated soon after the introduction of OA with dramatic overanticoagulation, OA overdose is mostly related to environmental factors.

Keywords

Cytochrome P450 2C9 Anticoagulants Overdose Drug interactions Polymorphism genetics Pharmacogenetics 

Notes

Acknowledgements

We are grateful to L. Dubert and C. Bernard for their technical assistance and the members of the Immunology and Hematology Department, Saint-Antoine Hospital, for their precious collaboration and their constant good mood. We also acknowledge the support of the "region Ile de France" through the program "SESAME".

References

  1. 1.
    Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR (1994) Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 4:39–42Google Scholar
  2. 2.
    Thijssen HH, Verkooijen IW, Frank HL (2000) The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogenetics 10:757–60Google Scholar
  3. 3.
    Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT (1999) Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 9:71–80Google Scholar
  4. 4.
    Brian WR, Srivastava PK, Umbenhauer DR, Lloyd RS, Guengerich FP (1989) Expression of a human liver cytochrome P-450 protein with tolbutamide hydroxylase activity in Saccharomyces cerevisiae. Biochemistry 28:4993–9Google Scholar
  5. 5.
    Stubbins MJ, Harries LW, Smith G, Tarbit MH, Wolf CR (1996) Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 6:429–39Google Scholar
  6. 6.
    Veronese ME, Doecke CJ, Mackenzie PI, McManus ME, Miners JO, Rees DL, et al. (1993) Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily. Biochem J 289:533–8Google Scholar
  7. 7.
    Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE (1996) Allelic variants of human cytochrome P450 2C9:baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 333:447–58Google Scholar
  8. 8.
    Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717–9Google Scholar
  9. 9.
    Landefeld CS, Beyth RJ (1993) Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 95:315–28Google Scholar
  10. 10.
    Verstuyft C, Morin S, Robert A, Eschewege V, Beaune P, Jaillon P, et al. (2001) Oral anticoagulant overdose risk factors. Thromb Haemost : Abstract P677Google Scholar
  11. 11.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41Google Scholar
  12. 12.
    Barcellona D, Vannini ML, Fenu L, Balestrieri C, Marongiu F (1998) Warfarin or acenocoumarol: which is better in the management of oral anticoagulants? Thromb Haemost 80:899–902Google Scholar
  13. 13.
    Sorano GG, Biondi G, Conti M, Mameli G, Licheri D, Marongiu F (1993) Controlled vitamin K content diet for improving the management of poorly controlled anticoagulated patients: a clinical practice proposal. Haemostasis 23:77–82Google Scholar
  14. 14.
    Freedman MD, Olatidoye AG (1994) Clinically significant drug interactions with the oral anticoagulants. Drug Saf 10:381–94Google Scholar
  15. 15.
    Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet Anal 14:143–9Google Scholar
  16. 16.
    Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, et al. (1993) Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 118:511–20Google Scholar
  17. 17.
    Costedoat-Chalumeau N, Amoura Z, Aymard G, Sevin O, Wechsler B, Cacoub P, et al. (2000) Potentiation of vitamin K antagonists by high-dose intravenous methylprednisolone. Ann Intern Med 132:631–5Google Scholar
  18. 18.
    Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman-Sundberg M, Sjoqvist F (1999) Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 254:628–31Google Scholar
  19. 19.
    Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A, et al. (2001) Interindividual variability in sensitivity to warfarin--Nature or nurture? Clin Pharmacol Ther 70:159–64Google Scholar
  20. 20.
    Qureshi GD, Reinders TP, Swint JJ, Slate MB (1981) Acquired warfarin resistance and weight-reducing diet. Arch Intern Med 141:507–9Google Scholar
  21. 21.
    Hirsh. Guidelines for Antithrombotic Therapy. Fourth Edition ed: Harcourt, 2001Google Scholar
  22. 22.
    Penning-Van Beest FJ, Van Meegen E, Rosendaal FR, Stricker BH (2001) Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol Ther 69:451–7Google Scholar
  23. 23.
    Bianco TM, Bussey HI, Farnett LE, Linn WD, Roush MK, Wong YW (1992) Potential warfarin-ciprofloxacin interaction in patients receiving long-term anticoagulation. Pharmacotherapy 12:435–9Google Scholar
  24. 24.
    Rocci ML, Jr., Vlasses PH, Distlerath LM, Gregg MH, Wheeler SC, Zing W, et al. (1990) Norfloxacin does not alter warfarin's disposition or anticoagulant effect. J Clin Pharmacol 30:728–32Google Scholar
  25. 25.
    Harder S, Thurmann P (1996) Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet 30:416–44Google Scholar
  26. 26.
    Loeliger EA, Van der Esch B, Mattern MJ, Hemker HC (1964) The biological disappearance rate of prothrombin, factors VII, IX and X from plasma in hypothyroidism, hyperthyroidism, and during fever. Thromb Diath Haemorrh 1:267–277Google Scholar
  27. 27.
    Caraco Y, Chajek-Shaul T (1989) The incidence and clinical significance of amiodarone and acenocoumarol interaction. Thromb Haemost 62:906–8Google Scholar
  28. 28.
    O'Reilly RA, Trager WF, Rettie AE, Goulart DA (1987) Interaction of amiodarone with racemic warfarin and its separated enantiomorphs in humans. Clin Pharmacol Ther 42:290–4Google Scholar
  29. 29.
    Tang C, Shou M, Rushmore TH, Mei Q, Sandhu P, Woolf EJ, et al. (2001) In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics. Pharmacogenetics 11:223–5Google Scholar
  30. 30.
    Yasar U, Tybring G, Hidestrand M, Oscarson M, Ingelman-Sundberg M, Dahl ML, et al. (2001) Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos 29:1051–6Google Scholar
  31. 31.
    Goldstein JA (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52:349–55Google Scholar
  32. 32.
    Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 96:1816–9Google Scholar
  33. 33.
    Hermida J, Zarza J, Alberca I, Montes R, Lopez ML, Molina E, et al. (2002) Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood 99:4237–9Google Scholar
  34. 34.
    Thijssen HH, Drittij MJ, Vervoort LM, de Vries-Hanje JC (2001) Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3. Clin Pharmacol Ther 70:292–8Google Scholar
  35. 35.
    Verstuyft C, Morin S, Robert A, Loriot MA, Beaune P, Jaillon P, et al. (2001) Early acenocoumarol overanticoagulation among cytochrome P450 2C9 poor metabolizers. Pharmacogenetics 11:735–7Google Scholar
  36. 36.
    Margaglione M, Colaizzo D, Andrea G, Brancaccio V, Ciampa A, Grandone. (2000) Genetic modulation of oral anticoagulation with warfarin. Thromb Haemos 84:775–778Google Scholar
  37. 37.
    Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF, et al. (1997) Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 7:361–7Google Scholar
  38. 38.
    Ogg MS, Brennan P, Meade T, Humphries SE (1999) CYP2C9*3 allelic variant and bleeding complications. Lancet 354:1124Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • C. Verstuyft
    • 1
  • A. Robert
    • 2
  • S. Morin
    • 1
  • M. A. Loriot
    • 3
  • A. Flahault
    • 4
  • P. Beaune
    • 3
  • C. Funck-Brentano
    • 1
  • P. Jaillon
    • 1
  • L. Becquemont
    • 1
  1. 1.Department of PharmacologySaint-Antoine Paris VI University and Assistance-Publique Hôpitaux de ParisParisFrance
  2. 2.Department of Immunology and HematologySaint-Antoine HospitalParisFrance
  3. 3.INSERM U490Centre Universitaire des Saint Pères, Paris UniversityParis VFrance
  4. 4.Department of StatisticSaint-Antoine Paris VI University and Assistance-Publique Hôpitaux de ParisParisFrance

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