title: Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment.
abstract: OBJECTIVE
  Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics.
  
  
  METHODS
  In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated.
  
  
  RESULTS
  A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure.
  
  
  CONCLUSIONS
  Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies.
authors.affiliation: Erasmus Medical Center-Daniel den Hood Cancer Center, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Anne-Joy M
authors.initials: AJ
authors.lastname: de Graan
authors.forename: Sebastiaan F
authors.initials: SF
authors.lastname: Teunissen
authors.forename: Filip Y F L
authors.initials: FY
authors.lastname: de Vos
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Felix E
authors.initials: FE
authors.lastname: de Jongh
authors.forename: Aad I
authors.initials: AI
authors.lastname: de Vos
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: van Alphen
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6