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.

  • Original Article
  • Published:

The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction

The Pharmacogenomics Journal volume 9, pages 34–41 (2009)Cite this article

Abstract

Polymorphisms of the cytochrome P450 2D6 (CYP2D6) gene affecting enzyme activity are involved in interindividual variability in drug efficiency/toxicity. Four phenotypic groups are found in the general population: ultra rapid (UM), extensive (EM), intermediate (IM) and poor (PM) metabolizers. The AmpliChip CYP450 test is the first genotyping array allowing simultaneous analysis of 33 CYP2D6 alleles. The main aim of this study was to evaluate the performance of this test in CYP2D6 phenotype prediction. We first verified the AmpliChip CYP450 test genotyping accuracy for five CYP2D6 alleles routinely analysed in our laboratory (alleles 3,4,5,6, × N; n=100). Results confirmed those obtained by real-time PCR. Major improvements using the array are the detection of CYP2D6 intermediate alleles and identification of the duplicated alleles. CYP2D6 phenotype was determined by assessing urinary elimination of dextromethorphan and its metabolite dextrorphan and compared to the array prediction (n=165). Although a low sensitivity of UM prediction by genotyping was observed, phenotype prediction was optimal for PM and satisfying for EM and IM.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • 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

Similar content being viewed by others

References

  1. Gardiner SJ, Begg EJ . Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58: 521–590.

    Article  CAS  PubMed  Google Scholar 

  2. Lin JH . Pharmacokinetic and pharmacodynamic variability: a daunting challenge in drug therapy. Curr Drug Metab 2007; 8: 109–136.

    Article  CAS  PubMed  Google Scholar 

  3. Lazarou J, Pomeranz BH, Corey PN . Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200–1205.

    Article  CAS  PubMed  Google Scholar 

  4. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004; 351: 2827–2831.

    Article  CAS  PubMed  Google Scholar 

  5. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ . Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006; 368: 704.

    Article  PubMed  Google Scholar 

  6. Chou WH, Yan FX, Robbins-Weilert DK, Ryder TB, Liu WW, Perbost C et al. Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships. Clin Chem 2003; 49: 542–551.

    Article  CAS  PubMed  Google Scholar 

  7. Dahl ML, Johansson I, Bertilsson L, Ingelman-Sundberg M, Sjoqvist F . Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274: 516–520.

    CAS  PubMed  Google Scholar 

  8. Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Morike K et al. Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population. Pharmacogenetics 1998; 8: 15–26.

    Article  CAS  PubMed  Google Scholar 

  9. Raimundo S, Fischer J, Eichelbaum M, Griese EU, Schwab M, Zanger UM . Elucidation of the genetic basis of the common ′intermediate metabolizer′ phenotype for drug oxidation by CYP2D6. Pharmacogenetics 2000; 10: 577–581.

    Article  CAS  PubMed  Google Scholar 

  10. Daali Y, Cherkaoui S, Doffey-Lazeyras F, Dayer P, Desmeules JA . Development and validation of a chemical hydrolysis method for dextromethorphan and dextrophan determination in urine samples: application to the assessment of CYP2D6 activity in fibromyalgia patients. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 861: 56–63.

    Article  CAS  PubMed  Google Scholar 

  11. Dalen P, Dahl ML, Bernal Ruiz ML, Nordin J, Bertilsson L . 10-Hydroxylation of nortriptyline in white persons with 0, 1, 2, 3, and 13 functional CYP2D6 genes. Clin Pharmacol Ther 1998; 63: 444–452.

    Article  CAS  PubMed  Google Scholar 

  12. Schmid B, Bircher J, Preisig R, Kupfer A . Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther 1985; 38: 618–624.

    Article  CAS  PubMed  Google Scholar 

  13. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS . The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 2008; 83: 234–242.

    Article  CAS  PubMed  Google Scholar 

  14. Heller T, Kirchheiner J, Armstrong VW, Luthe H, Tzvetkov M, Brockmoller J et al. AmpliChip CYP450 GeneChip: a new gene chip that allows rapid and accurate CYP2D6 genotyping. Ther Drug Monit 2006; 28: 673–677.

    Article  CAS  PubMed  Google Scholar 

  15. Sachse C, Brockmoller J, Hildebrand M, Muller K, Roots I . Correctness of prediction of the CYP2D6 phenotype confirmed by genotyping 47 intermediate and poor metabolizers of debrisoquine. Pharmacogenetics 1998; 8: 181–185.

    Article  CAS  PubMed  Google Scholar 

  16. McElroy S, Sachse C, Brockmoller J, Richmond J, Lira M, Friedman D et al. CYP2D6 genotyping as an alternative to phenotyping for determination of metabolic status in a clinical trial setting. AAPS PharmSci 2000; 2: E33.

    Article  CAS  PubMed  Google Scholar 

  17. McMasters DR, Torres RA, Crathern SJ, Dooney DL, Nachbar RB, Sheridan RP et al. Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules. J Med Chem 2007; 50: 3205–3213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hellum BH, Nilsen OG . The in vitro inhibitory potential of trade herbal products on human CYP2D6-mediated metabolism and the influence of ethanol. Basic Clin Pharmacol Toxicol 2007; 101: 350–358.

    Article  CAS  PubMed  Google Scholar 

  19. de Leon J . The crucial role of the therapeutic window in understanding the clinical relevance of the poor versus the ultrarapid metabolizer phenotypes in subjects taking drugs metabolized by CYP2D6 or CYP2C19. J Clin Psychopharmacol 2007; 27: 241–245.

    Article  PubMed  Google Scholar 

  20. Chladek J, Zimova G, Martinkova J, Tuma I . Intra-individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects. Fundam Clin Pharmacol 1999; 13: 508–515.

    Article  CAS  PubMed  Google Scholar 

  21. Furman KD, Grimm DR, Mueller T, Holley-Shanks RR, Bertz RJ, Williams LA et al. Impact of CYP2D6 intermediate metabolizer alleles on single-dose desipramine pharmacokinetics. Pharmacogenetics 2004; 14: 279–284.

    Article  CAS  PubMed  Google Scholar 

  22. Steimer W, Zopf K, von Amelunxen S, Pfeiffer H, Bachofer J, Popp J et al. Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers. Clin Chem 2004; 50: 1623–1633.

    Article  CAS  PubMed  Google Scholar 

  23. Lovlie R, Daly AK, Matre GE, Molven A, Steen VM . Polymorphisms in CYP2D6 duplication-negative individuals with the ultrarapid metabolizer phenotype: a role for the CYP2D6*35 allele in ultrarapid metabolism? Pharmacogenetics 2001; 11: 45–55.

    Article  CAS  PubMed  Google Scholar 

  24. de Leon J . AmpliChip CYP450 test: personalized medicine has arrived in psychiatry. Expert Rev Mol Diagn 2006; 6: 277–286.

    Article  CAS  PubMed  Google Scholar 

  25. Frank D, Jaehde U, Fuhr U . Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol 2007; 63: 321–333.

    Article  CAS  PubMed  Google Scholar 

  26. Muller B, Zopf K, Bachofer J, Steimer W . Optimized strategy for rapid cytochrome P450 2D6 genotyping by real-time long PCR. Clin Chem 2003; 49: 1624–1631.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from the Swiss National Science Foundation (NRP53-4049-405340-104645/1). Roche Diagnostics provided the AmpliChip CYP450 test at no cost to the study.

Author information

Authors and Affiliations

  1. Service of Laboratory Medicine, University Hospitals, Geneva, Switzerland

    M C Rebsamen, A Chiappe, A Diemand, C Rey, D Hochstrasser & M F Rossier

  2. Service of Clinical Pharmacology and Toxicology, University Hospitals, Geneva, Switzerland

    J Desmeules, Y Daali, J Chabert & P Dayer

Authors
  1. M C Rebsamen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Desmeules
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Daali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Chiappe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Diemand
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Rey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Chabert
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Dayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Hochstrasser
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M F Rossier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M C Rebsamen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rebsamen, M., Desmeules, J., Daali, Y. et al. The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J 9, 34–41 (2009). https://doi.org/10.1038/tpj.2008.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2008.7

Keywords

This article is cited by

Search

Advanced search

Quick links