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Thromb Haemost 2004; 91(01): 95-101
DOI: 10.1160/TH03-05-0325
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype

Karen N. van Dijk
1   Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
2   Department of Clinical Pharmacy, Medical Centre Leeuwarden, The Netherlands
,
Arian W. Plat
1   Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
,
Alieke A. C. van Dijk
1   Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
,
Margriet Piersma-Wichers
3   Groningen Thrombosis Service, Groningen, The Netherlands
,
Anne M. B. de Vries-Bots
4   Pharmacy ‘t Hooge Zand, Hoogezand, The Netherlands
,
Jennita Slomp
5   Department of Clinical Chemistry, Stichting Klinisch Chemisch Laboratorium, Leeuwarden, The Netherlands
,
Lolkje T.W. de Jong-van den Berg
1   Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
,
Jacobus R. B. J. Brouwers
1   Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
2   Department of Clinical Pharmacy, Medical Centre Leeuwarden, The Netherlands
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Publikationsverlauf

Received 29. Mai 2003

Accepted after resubmission 17. September 2003

Publikationsdatum:
30. November 2017 (online)

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Summary

NSAIDs are reported to increase the risk of bleeding in coumarin users. The mechanism underlying this risk is inhibition of platelet aggregation, however a pharmacokinetic mechanism resulting in an increased International Normalised Ratio (INR) was proposed in some case reports in warfarin treated patients. In this retrospective cohort study the influence of diclofenac, naproxen and ibuprofen on the INR of outpatients stabilised on acenocoumarol therapy was investigated. We also determined the role of cytochrome P450 2C9 (CYP2C9) polymorphism on coumarin dosage and INR in NSAID users. The study was carried out at the Groningen Outpatient Thrombosis Service. A retrospective cohort study among patients who received both acenocoumarol and one of the NSAIDs under study was performed. Patients whose INR rose above the upper level of the therapeutic range (INR above 3.5 or 4.0) after an NSAID under study was added to the acenocoumarol therapy, were compared with patients who did not show such an elevation. A two-sample t-test (average acenocoumarol dosage, age), and chi-square tests (sex, therapeutic range, type of NSAID) were used to test for differences. Genotyping was carried out by analysing blood samples for the relevant CYP2C9 alleles. The study population consisted of 112 patients on stable acenocoumarol therapy, of which 52 (46%) showed an elevation of the INR above the desired therapeutic level (INR3.5 and 4.0 respectively) after the start of an NSAID under study. In 12 patients, the INR increased above 6. The INR of the other 60 patients (54%) remained constant after the start of one of the NSAIDs under study. There were no statistically significant differences between patients with increased INR and patients without increased INR with regard to age, sex, therapeutic range and average acenocoumarol dosage. Eighty patients, of whom 36 showed an increased INR as a result of a potential acenocoumarol-NSAID drug interaction, were included in the genotyping study. No association between CYP2C9 genotype and an increased INR as a result of the drug-drug interaction was found. In nearly half of a cohort of elderly patients, the INR increased beyond the therapeutic range (INR 3.5 or 4.0) as a result of a potential pharmacokinetic drug-drug interaction between acenocoumarol and diclofenac, naproxen and ibuprofen. The average increase in INR was between 1 and 4. Polymorphism of CYP2C9 does not seem to be a relevant risk factor for the NSAID-acenocoumarol interaction.

Keywords

Acenocoumarol - NSAIDs - drug-interaction - CYP2C9
 

  • References

  • 1 Hirsch J. Oral anticoagulant drugs. New Engl J Med 1991; 324: 1865-75.
    CrossrefPubMedSuche in Google Scholar
  • 2 Van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. Arch Intern Med 1993; 153: 1557-62.
    CrossrefPubMedSuche in Google Scholar
  • 3 Harder S, Thürmann P. Clinically important drug interactions with anticoagulants. An update. Clin Pharmacokinet 1996; 30: 416-44.
    CrossrefPubMedSuche in Google Scholar
  • 4 Brouwers JRBJ, De Smet PAGM. Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 1994; 27: 462-85.
    CrossrefPubMedSuche in Google Scholar
  • 5 Commissie Interacterende Medicatie Cumarines. Standaard afhandeling cumarineinteracties (in Dutch). Wetenschappelijk Instituut Nederlandse Apothekers (WINAp). The Hague; The Netherlands: 1999
    Suche in Google Scholar
  • 6 Breukink-Engbers WG. Monitoring therapy with anticoagulants in the Netherlands. Semin Tromb Hemost 1999; 25: 37-42.
    PubMedSuche in Google Scholar
  • 7 Philips KA, Veenstra DL, Oren E. et al. Potential role of pharmacogenomics in reducing adverse drug reactions. JAMA 2001; 286: 2270-9.
    CrossrefPubMedSuche in Google Scholar
  • 8 Roland CWolf, Smith G, Smith RL. Pharmacogenetics. BMJ 2000; 320: 987-90.
    CrossrefPubMedSuche in Google Scholar
  • 9 Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet 2000; 356: 1667-71.
    CrossrefPubMedSuche in Google Scholar
  • 10 Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos 2000; 28: 1284-90.
    PubMedSuche in Google Scholar
  • 11 Klose TS, Ibaenu GC, Ghanayem BI. et al. Identification of residues 286 and 289 as critical for conferring substrate specificity of human CYP2C9 for diclofenac and ibuprofen. Arch Biochem Biophys 1998; 357: 420-8.
    PubMedSuche in Google Scholar
  • 12 Bliesath H, Huber R, Steinijans VW, Koch HJ, Wurst W, Mascher H. Lack of pharmacokinetic interaction between pantoprazole and diclofenac. Int J Clin Pharmacol Ther 1996; 34 (Suppl. 01) S76-S80.
    PubMedSuche in Google Scholar
  • 13 Leemann T, Transon C, Dayer P. Cytochrome P450 TB (2C9): a major monooxygenase catalyzing diclofenac 4’-hydroxylation in human liver. Life Sci 1993; 52: 29-34.
    CrossrefPubMedSuche in Google Scholar
  • 14 Miners JO, Coulter D, Tukey RH. et al. Cytochromes P450, 1A2 and 2C9 are responsible for the human hepatic O-demethylation of R- and S-naproxen. Biochem Pharmacol 1996; 51: 1003-8.
    CrossrefPubMedSuche in Google Scholar
  • 15 Sotaniemi EA, Arranto AJ, Pelkonen O. et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathological conditions. Clin Pharmacol Ther 1997; 61: 331-9.
    CrossrefPubMedSuche in Google Scholar
  • 16 Trombotest. In: Van Leusden HAIM. ed. Diagnostisch Kompas. The Netherlands: College voor Zorgverzekeringen; 2003: 769-70.
    Suche in Google Scholar
  • 17 Wang S-L, Huang J-D, Lai M-D. et al. Detection of CYP2C9 polymorphism based on polymerase chain reaction in Chinese. Pharmacogenetics 1995; 05: 37-42.
    CrossrefPubMedSuche in Google Scholar
  • 18 Steward D, Haining RL, Henne KR. et al. Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 1997; 07: 361-7.
    CrossrefPubMedSuche in Google Scholar
  • 19 Hylek EM, Chang YC, Skates SJ. et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000; 160: 1612-7.
    CrossrefPubMedSuche in Google Scholar
  • 20 Tassies D, Freire C, Pijoan J. et al. Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation. Haematology 2002; 87: 1185-91.
    PubMedSuche in Google Scholar
  • 21 Thijssen HHW, Verkooyen IWC, Frank HLL. The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogenetics 2000; 10: 1-4.
    CrossrefPubMedSuche in Google Scholar
  • 22 Van der Heijden JF, Schmits S, Remkes MGH. et al. CYP2C9 Polymorphisms impair acenocoumarol metabolism, but do not increase bleeding risk. Blood 2002; 100: 149a.
    PubMedSuche in Google Scholar
  • 23 Hermida J, Zarza J, Alberca I. et al. Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol. Blood 2002; 99: 4237-9.
    CrossrefPubMedSuche in Google Scholar
  • 24 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: 1816-19.
    PubMedSuche in Google Scholar
  • 25 Aithal GP, Day CP, Kesteven PJ. et al. Association of polymorphism in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-9.
    CrossrefPubMedSuche in Google Scholar
  • 26 Knijff-Dutmer EAJ, Schut GA, van de Laar AFJ. Concomitant coumarin-NSAID therapy and risk for bleeding. Ann Pharmacother 2003; 37: 12-6.
    CrossrefPubMedSuche in Google Scholar
  • 27 Bonnabry P, Desmeules J, Rudaz S. et al. Stereoselective interaction beween piroxicam and acenocoumarol. Br J Clin Pharmacol 1996; 41: 525-30.
    PubMedSuche in Google Scholar
  • 28 Pardo A, Garcia-Losa M, Fernandez-Pavon A. et al. A placebo-controlled study of interaction between nabumetone and acenocoumarol. Br J Clin Pharmacol 1999; 47: 441-4.
    CrossrefPubMedSuche in Google Scholar
  • 29 Masche UP, Rentsch KM, von Felten A. et al. No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics. Eur J Clin Pharmacol 1999; 54: 865-8.
    CrossrefPubMedSuche in Google Scholar
  • 30 Chan TY. Prolongation of prothrombin time with the use of indomethacin and warfarin. Br J Clin Pract 1997; 51: 177-8.
    PubMedSuche in Google Scholar
  • 31 Karim A, Tolber D, Piergies A. et al. Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects. J Clin Pharmacol 2000; 40: 655-63.
    CrossrefPubMedSuche in Google Scholar
  • 32 Haasse KK, Rojas-Fernandez CH, Lane L. et al. Potential interaction between celecoxib and warfarin (letter). Ann Pharmacother 2000; 34: 666-7.
    CrossrefPubMedSuche in Google Scholar
  • 33 Mersfelder TL, Stewart LR. Warfarin and celecoxib interaction. Ann Pharmacother 2000; 34: 325-7.
    CrossrefPubMedSuche in Google Scholar
  • 34 Stading JA, Skrabal MZ, Faulkner MA. Seven cases of interaction between warfarin and cyclooxygenase-2 inhibitors. Am J Health-Syst Pharm 2001; 58: 2076-80.
    PubMedSuche in Google Scholar
  • 35 Schaefer MG, Plowman BK, Morreale AP. et al. Interaction of rofecoxib and celecoxib with warfarin. Am J Health-Syst Pharm 2003; 60: 1319-23.
    PubMedSuche in Google Scholar