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

Author:

Tay-Sontheimer Jessica1,Shireman Laura M1,Beyer Richard P2,Senn Taurence1,Witten Daniela3,Pearce Robin E4,Gaedigk Andrea45,Gana Fomban Cletus L1,Lutz Justin D1,Isoherranen Nina1,Thummel Kenneth E1,Fiehn Oliver6,Leeder J Steven45,Lin Yvonne S1

Affiliation:

1. Department of Pharmaceutics, University of Washington, Seattle, WA, USA

2. Center for Ecogenetics & Environmental Health, University of Washington, Seattle, WA, USA

3. Department of Biostatistics, University of Washington, Seattle, WA, USA

4. Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Hospitals & Clinics, Kansas City, MO, USA

5. Department of Pediatrics, University of Missouri-Kansas City, Kansas City, MO, USA

6. UC Davis Genome Center, University of California Davis, Davis, CA, USA

Abstract

Aim: We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. Patients & 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. Conclusion: Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping.

Publisher

Future Medicine Ltd

Subject

Pharmacology,Genetics,Molecular Medicine

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