title: Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics.
abstract: OBJECTIVE
  We sought to discover endogenous urinary biomarkers of human CYP2D6 activity.
  
  
  METHODS
  Healthy pediatric subjects (n = 189) were phenotyped using dextromethorphan and randomized for candidate biomarker selection and validation. Global urinary metabolomics was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Candidate biomarkers were tested in adults receiving fluoxetine, a CYP2D6 inhibitor.
  
  
  RESULTS
  A biomarker, M1 (m/z 444.3102) was correlated with CYP2D6 activity in both the pediatric training and validation sets. Poor metabolizers had undetectable levels of M1, whereas it was present in subjects with other phenotypes. In adult subjects, a 9.56-fold decrease in M1 abundance was observed during CYP2D6 inhibition.
  
  
  CONCLUSIONS
  Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tay-Sontheimer
authors.forename: Laura M
authors.initials: LM
authors.lastname: Shireman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.forename: Taurence
authors.initials: T
authors.lastname: Senn
authors.forename: Daniela
authors.initials: D
authors.lastname: Witten
authors.forename: Robin E
authors.initials: RE
authors.lastname: Pearce
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: Cletus L
authors.initials: CL
authors.lastname: Gana Fomban
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lutz
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000652:urine*; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000008:administration & dosage; D003915:Dextromethorphan / Q000652:urine; D003917:Dextrorphan / Q000652:urine; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D055432:Metabolomics
chemical_list: D015415:Biomarkers; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D005473:Fluoxetine; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6; biomarker; clinical; dextromethorphan; endogenous; fluoxetine; metabolomics; pediatric; phenotype