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.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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Vol. 15, No. 16

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Published online 18 December 2014

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Acknowledgements

The authors would like to thank K Kerr (University of Washington, Seattle, WA, USA) for her statistical consultation.

Financial & competing interests disclosure

This research was supported in part by the NIH R01 HD058556 (to JS Leeder and YS Lin), Pharmacological Sciences Training grant T32 GM007750 (to J Tay-Sontheimer), NIEHS Center grants P30 ES07033 (to RP Beyer and YS Lin), Clinical and Translational Science Award UL1TR000423 (pilot funds to YS Lin), CTSA KL2 TR000421 (to YS Lin) and University of Washington School of Pharmacy DMTPR funding. Clinical support for the study was provided by a supplement from CTSA UL1 TR000001 (formerly UL1 RR033179), Heartland Institute for Clinical and Translational Research (HICTR). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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