title: Endoxifen levels and its association with CYP2D6 genotype and phenotype: evaluation of a southern Brazilian population under tamoxifen pharmacotherapy.
abstract: BACKGROUND
  An association between CYP2D6 variation and clinical outcomes among women with breast cancer treated with tamoxifen (TAM) has been demonstrated, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes. This association is mainly due to the CYP2D6-mediated hydroxylation of N-desmethyltamoxifen (NDT) to yield endoxifen (EDF), which because of its high antiestrogenic potency, is mainly responsible for the therapeutic efficacy of TAM. The aim of this study was to evaluate the relation of CYP2D6 genotyping and phenotyping with EDF levels and [NDT]/[EDF] metabolic ratio in breast cancer patients from South of Brazil under TAM therapy.
  
  
  METHODS
  Trough blood samples were collected from 97 patients. CYP2D6 genotyping was performed with a luminex assay and calculation of genotypic activity scores. Tamoxifen and metabolites EDF, NDT, and 4-hydroxy-TAM were measured in plasma by high performance liquid chromatography with photo diode array detector. CYP2D6 phenotyping was performed by the determination of dextromethorphan (DMT) and dextrorphan (DTF) by high-performance liquid chromatography with fluorescence detection at plasma collected 3 hours after oral administration of 33 mg of DMF. Phenotypes were given according to [DMT]/[DTF] metabolic ratio.
  
  
  RESULTS
  CYP2D6 genotyping indicated a prevalence of 4.1% poor metabolizer, 4.1% intermediate metabolizer, 49.5% extensive metabolizer slow activity, 39.2% extensive metabolizer fast activity, and 3.1% ultrarapid metabolizer. Genotype (genotypic activity scores) was significantly correlated with phenotype ([DMT]/[DTF]), with a moderate association (rs = -0.463; P < 0.001). Median plasma concentrations (nanograms per milliliter; N = 97) were TAM 57.17; 4-hydroxy-TAM 1.01; EDF 6.21; NDT 125.50. EDF levels were lower in poor metabolizers than that in extensive metabolizers (P < 0.05). Phenotype showed stronger, but still moderate, association with EDF and [NDT]/[EDF] than genotype (r = -0.507, r = 0.625, P < 0.001 versus r = 0.356, r = 0.516, P < 0.01). Phenotype accounted for 26% of the variability in EDF levels and 38% of [NDT]/[EDF], whereas genotype accounted for 12% and 27%, respectively.
  
  
  CONCLUSIONS
  CYP2D6 genotyping and/or phenotyping could not fully predict EDF concentrations. Monitoring EDF itself could be considered during TAM therapy.
authors: Pós Graduação em Medicina, Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. marinaantunes@feevale.br
authors: Marina V
authors: MV
authors: Antunes
authors: Rafael
authors: R
authors: Linden
authors: Tamyris V
authors: TV
authors: Santos
authors: Pierre
authors: P
authors: Wallemacq
authors: Vincent
authors: V
authors: Haufroid
authors: Jean-François
authors: JF
authors: Classen
authors: Huander
authors: H
authors: Andreolla
authors: Nathalia
authors: N
authors: Costa
authors: Tiago O
authors: TO
authors: Fontanive
authors: Daniela D
authors: DD
authors: Rosa
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001938:Brazil; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003915:Dextromethorphan / Q000097:blood; D003917:Dextrorphan / Q000097:blood; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008875:Middle Aged; D010641:Phenotype; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003917:Dextrorphan; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; C028787:N-desmethyltamoxifen