In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles

Daniel L. Hertz, Anna C. Snavely, Howard L. McLeod, Christine M. Walko, Joseph G. Ibrahim, Steven Anderson, Karen E. Weck, Gustav Magrinat, Oludamilola Olajide, Susan Moore, Rachel Raab, Daniel R. Carrizosa, Steven Corso, Garry Schwartz, Jeffrey M. Peppercorn, James P. Evans, David R. Jones, Zeruesenay Desta, David A. Flockhart, Lisa A. Carey & 1 others William J. Irvin

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Abstract

Aims A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. Methods Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen: N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively. Results Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P <0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P <0.0001), with the CYP2D62 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014). Conclusion The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.

Original languageEnglish (US)
Pages (from-to)1122-1130
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Volume80
Issue number5
DOIs
StatePublished - Nov 1 2015

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Cytochrome P-450 CYP2D6
Alleles
Tamoxifen
Phenotype
Genotype

Keywords

  • activity score
  • CYP2D6
  • endoxifen
  • N-desmethyl-tamoxifen
  • pharmacogenetic
  • tamoxifen

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Hertz, D. L., Snavely, A. C., McLeod, H. L., Walko, C. M., Ibrahim, J. G., Anderson, S., ... Irvin, W. J. (2015). In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles. British Journal of Clinical Pharmacology, 80(5), 1122-1130. https://doi.org/10.1111/bcp.12665

In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles. / Hertz, Daniel L.; Snavely, Anna C.; McLeod, Howard L.; Walko, Christine M.; Ibrahim, Joseph G.; Anderson, Steven; Weck, Karen E.; Magrinat, Gustav; Olajide, Oludamilola; Moore, Susan; Raab, Rachel; Carrizosa, Daniel R.; Corso, Steven; Schwartz, Garry; Peppercorn, Jeffrey M.; Evans, James P.; Jones, David R.; Desta, Zeruesenay; Flockhart, David A.; Carey, Lisa A.; Irvin, William J.

In: British Journal of Clinical Pharmacology, Vol. 80, No. 5, 01.11.2015, p. 1122-1130.

Research output: Contribution to journalArticle

Hertz, DL, Snavely, AC, McLeod, HL, Walko, CM, Ibrahim, JG, Anderson, S, Weck, KE, Magrinat, G, Olajide, O, Moore, S, Raab, R, Carrizosa, DR, Corso, S, Schwartz, G, Peppercorn, JM, Evans, JP, Jones, DR, Desta, Z, Flockhart, DA, Carey, LA & Irvin, WJ 2015, 'In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles', British Journal of Clinical Pharmacology, vol. 80, no. 5, pp. 1122-1130. https://doi.org/10.1111/bcp.12665
Hertz DL, Snavely AC, McLeod HL, Walko CM, Ibrahim JG, Anderson S et al. In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles. British Journal of Clinical Pharmacology. 2015 Nov 1;80(5):1122-1130. https://doi.org/10.1111/bcp.12665
Hertz, Daniel L. ; Snavely, Anna C. ; McLeod, Howard L. ; Walko, Christine M. ; Ibrahim, Joseph G. ; Anderson, Steven ; Weck, Karen E. ; Magrinat, Gustav ; Olajide, Oludamilola ; Moore, Susan ; Raab, Rachel ; Carrizosa, Daniel R. ; Corso, Steven ; Schwartz, Garry ; Peppercorn, Jeffrey M. ; Evans, James P. ; Jones, David R. ; Desta, Zeruesenay ; Flockhart, David A. ; Carey, Lisa A. ; Irvin, William J. / In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles. In: British Journal of Clinical Pharmacology. 2015 ; Vol. 80, No. 5. pp. 1122-1130.
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AU - Hertz, Daniel L.

AU - Snavely, Anna C.

AU - McLeod, Howard L.

AU - Walko, Christine M.

AU - Ibrahim, Joseph G.

AU - Anderson, Steven

AU - Weck, Karen E.

AU - Magrinat, Gustav

AU - Olajide, Oludamilola

AU - Moore, Susan

AU - Raab, Rachel

AU - Carrizosa, Daniel R.

AU - Corso, Steven

AU - Schwartz, Garry

AU - Peppercorn, Jeffrey M.

AU - Evans, James P.

AU - Jones, David R.

AU - Desta, Zeruesenay

AU - Flockhart, David A.

AU - Carey, Lisa A.

AU - Irvin, William J.

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N2 - Aims A prospectively enrolled patient cohort was used to assess whether the prediction of CYP2D6 phenotype activity from genotype data could be improved by reclassification of diplotypes or alleles. Methods Three hundred and fifty-five patients receiving tamoxifen 20 mg were genotyped for CYP2D6 and tamoxifen metabolite concentrations were measured. The endoxifen: N-desmethly-tamoxifen metabolic ratio, as a surrogate of CYP2D6 activity, was compared across four diplotypes (EM/IM, EM/PM, IM/IM, IM/PM) that are typically collapsed into an intermediate metabolizer (IM) phenotype. The relative metabolic activity of each allele type (UM, EM, IM, and PM) and each EM and IM allele was estimated for comparison with the activity scores typically assigned, 2, 1, 0.5 and 0, respectively. Results Each of the four IM diplotypes have distinct CYP2D6 activity from each other and from the EM and PM phenotype groups (each P <0.05). Setting the activity of an EM allele at 1.0, the relative activities of a UM, IM and PM allele were 0.85, 0.67 and 0.52, respectively. The activity of the EM alleles were statistically different (P <0.0001), with the CYP2D62 allele (scaled activity = 0.63) closer in activity to an IM than an EM allele. The activity of the IM alleles were also statistically different (P = 0.014). Conclusion The current systems for translating CYP2D6 genotype into phenotype are not optimally calibrated, particularly in regards to IM diplotypes and the2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.

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