Skip to main content
SpringerLink
Log in

Increased liability of tramadol–warfarin interaction in individuals with mutations in the cytochrome P 450 2D6 gene

  • Short Communication
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

This study aimed to investigate the importance of cytochrome P 450 enzymes for the reported interaction between tramadol and warfarin.

Materials and methods

Cases of suspected interaction between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had been genotyped for known polymorphisms of CYP2D6, CYP2C9 and CYP2C19.

Results

Seven of ten patients carried defective CYP2D6 alleles (population prevalence 42.2%) (one-sided binomial test, P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6 enzyme inhibition.

Conclusion

The liability to an interaction between tramadol and warfarin may be related to the CYP2D6 activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

References

  1. Paar WD, Poche S, Gerloff J, Dengler HJ (1997) Polymorphic CYP2D6 mediates O-demethylation of the opioid analgesic tramadol. Eur J Clin Pharmacol 53:235–239

    Article  CAS  PubMed  Google Scholar 

  2. Scher ML, Huntington NH, Vitillo JA (1997) Potential interaction between tramadol and warfarin. Ann Pharmacother 31:646–647

    CAS  PubMed  Google Scholar 

  3. Sabbe JR, Sims PJ, Sims MH (1998) Tramadol-warfarin interaction. Pharmacotherapy 18:871–873

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Yamada H, Dahl M-L, Lannfelt L, Viitanen M, Winblad B, Sjöqvist F (1998) CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol 54:479–481

    CAS  PubMed  Google Scholar 

  6. Chang M, Dahl M-L, Tybring G, Gotharson E, Bertilsson L (1995). Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics 5:358–363

    CAS  PubMed  Google Scholar 

  7. Heim M, Meyer UA (1990) Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 336:529–532

    CAS  PubMed  Google Scholar 

  8. Bertilsson L (2001) Current status: pharmacogenetics/drug metabolism. In: Kalow W, Meyer UA, Tyndale RF (eds) Pharmacogenomics. Marcel Dekker Inc., New York, pp 33–50

  9. Meyer UA (2001) Pharmacogenetics: clinical viewpoints. In: Kalow W, Meyer UA, Tyndale RF (eds) Pharmacogenomics. Marcel Dekker Inc., New York, pp 135–150

  10. Postlind H, Danielson A, Lindgren A, Andersson SH (1998) Tolterodine, a new muscarinic receptor antagonist, is metabolized by cytochromes P 450 2D6 and 3A in human liver microsomes. Drug Metab Dispos 26:289–293

    CAS  PubMed  Google Scholar 

  11. Sindrup SH, Brosen K, Hansen MG, Aaes-Jorgensen T, Overo KF, Gram LF (1993) Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. Ther Drug Monit 15:11–17

    CAS  PubMed  Google Scholar 

  12. He N, Zhang WQ, Stockley D, Edeki T (2002) Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes. Eur J Clin Pharmacol 57:847–851

    Article  CAS  PubMed  Google Scholar 

  13. Yue QY, Säwe J (1997) Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes. Eur J Clin Pharmacol 52:41–47

    Article  CAS  PubMed  Google Scholar 

  14. Gan SH, Ismail R, Wan Adnan WA, Wan Z (2002) Correlation of tramadol pharmacokinetics and CYP2D6*10 genotype in Malaysian subjects. J Pharm Biomed Anal 30:189–195

    Article  CAS  PubMed  Google Scholar 

  15. Abdel-Rahman SM, Leeder JS, Wilson JT, Gaedigk A, Gotschall RR, Medve R et al (2002) Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation. J Clin Pharmacol 42:24–29

    Article  CAS  PubMed  Google Scholar 

  16. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP et al (2001) Identification of cytochrome P 450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 29:1146–1155

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Kaminsky LS, Zhang ZY (1997) Human P 450 metabolism of warfarin. Pharmacol Ther 73:67–74

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Schwartz JI, Bugianesi KJ, Ebel DL, De Smet M, Haesen R, Larson PJ et al (2000) The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin. Clin Pharmacol Ther 68:626–636

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The study was funded by a research grant from the Swedish Science Council (Medicine 04496).

Author information

Authors and Affiliations

  1. Drug Epidemiology Unit, Medical Products Agency, 75103 , Uppsala, Sweden

    Karin Hedenmalm

  2. Division of Clinical Pharmacology, Karolinska University Hospital (Huddinge), 14186 , Stockholm, Sweden

    Jonatan D. Lindh

  3. The Swedish Council on Technology Assessment in Health Care, 11486 , Stockholm, Sweden

    Juliette Säwe

  4. Division of Clinical Pharmacology, Karolinska University Hospital (Huddinge), 141 86 , Stockholm, Sweden

    Anders Rane

Authors
  1. Karin Hedenmalm
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonatan D. Lindh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juliette Säwe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anders Rane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karin Hedenmalm.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hedenmalm, K., Lindh, J.D., Säwe, J. et al. Increased liability of tramadol–warfarin interaction in individuals with mutations in the cytochrome P 450 2D6 gene. Eur J Clin Pharmacol 60, 369–372 (2004). https://doi.org/10.1007/s00228-004-0783-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-004-0783-7

Keywords

Search

Navigation