title: In vivo assessment of the metabolic activity of CYP2D6 diplotypes and alleles.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Michigan, Ann Arbor, MI48109-1065, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Hertz
authors.affiliation: RTI International, Research Triangle Park, NC, 27709-2194, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Snavely
authors.affiliation: Moffitt Cancer Center, Tampa, FL, 33612, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.affiliation: Moffitt Cancer Center, Tampa, FL, 33612, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Walko
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.affiliation: Laboratory Corporation of America, Burlington, NC, 27215, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Anderson
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
authors.affiliation: Moses Cone Health Cancer Center, Greensboro, NC, 27401-1020, USA.
authors.forename: Gustav
authors.initials: G
authors.lastname: Magrinat
authors.affiliation: Rex Hematology Oncology Associates, Raleigh, NC, 27607, USA.
authors.forename: Oludamilola
authors.initials: O
authors.lastname: Olajide
authors.affiliation: Rex Hematology Oncology Associates, Raleigh, NC, 27607, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Moore
authors.affiliation: Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Raab
authors.affiliation: Levine Cancer Institute, Charlotte, NC, 28204, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carrizosa
authors.affiliation: Palmetto Hematology Oncology, Spartanburg, SC, 29303, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Corso
authors.affiliation: Levine Cancer Institute Concord, Concord, NC, 28025, USA.
authors.forename: Garry
authors.initials: G
authors.lastname: Schwartz
authors.affiliation: Duke Cancer Institute, Durham, NC, 27705, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peppercorn
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Evans
authors.affiliation: Indiana University, Bloomington, IN, 47405, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Indiana University, Bloomington, IN, 47405, USA.
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Indiana University, Bloomington, IN, 47405, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.|Bon Secours Cancer Institute, Richmond, VA, 23230, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Irvin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D013629:Tamoxifen / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; N-desmethyl-tamoxifen; activity score; endoxifen; pharmacogenetic; tamoxifen