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In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles
Author(s) -
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.
Publication year - 2015
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12665
Subject(s) - allele , cyp2d6 , genotype , pharmacogenetics , allele frequency , medicine , pharmacogenomics , phenotype , genetics , biology , pharmacology , gene
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 CYP2D6* 2 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 the *2 allele. Additional research is needed to improve the prediction of CYP2D6 activity from genetic data for individualized dosing of CYP2D6 dependent drugs.