Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics

We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. 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...

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Published inPharmacogenomics Vol. 15; no. 16; pp. 1947 - 1962
Main Authors Tay-Sontheimer, Jessica, Shireman, Laura M, Beyer, Richard P, Senn, Taurence, Witten, Daniela, Pearce, Robin E, Gaedigk, Andrea, Gana Fomban, Cletus L, Lutz, Justin D, Isoherranen, Nina, Thummel, Kenneth E, Fiehn, Oliver, Leeder, J Steven, Lin, Yvonne S
Format Journal Article
LanguageEnglish
Published England Future Medicine Ltd 01.12.2014
Subjects
Adolescent
Adult
Biological markers
biomarker
Biomarkers - urine
Child
clinical
CYP2D6
Cytochrome P-450
Cytochrome P-450 CYP2D6 - genetics
Cytochrome P-450 CYP2D6 Inhibitors - administration & dosage
dextromethorphan
Dextromethorphan - urine
Dextrorphan - urine
endogenous
Female
fluoxetine
Fluoxetine - administration & dosage
Healthy Volunteers
Humans
Identification and classification
Innovations
Male
Metabolomics
pediatric
phenotype
Phenotypes
Properties
Urinalysis
phenotype
endogenous
clinical
fluoxetine
CYP2D6
metabolomics
biomarker
dextromethorphan
pediatric
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ISSN1462-2416
1744-8042
1744-8042
DOI10.2217/pgs.14.155

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Summary:We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. 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. 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. Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping.
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ISSN:1462-2416
1744-8042
1744-8042
DOI:10.2217/pgs.14.155