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METABOLOMICS REVEALS FIVE ENDOGENOUS BIOMARKERS IN HUMAN URINE AND PLASMA TO PREDICT CYP2D6 ACTIVITY
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  • Gaëlle Magliocco,
  • Jules Desmeules,
  • Alain Matthey,
  • Nasim Bararpour,
  • Timothée Joye,
  • Yvonne Gloor,
  • Aurélien Thomas,
  • Youssef Daali
Gaëlle Magliocco
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals
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Jules Desmeules
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals
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Alain Matthey
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals
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Nasim Bararpour
Forensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University Hospitals
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Timothée Joye
Forensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University Hospitals
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Yvonne Gloor
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals
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Aurélien Thomas
Forensic Toxicology and Chemistry Unit, CURML, Lausanne University Hospital, Geneva University Hospitals
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Youssef Daali
Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals
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Abstract

Background and Purpose: Individualized assessment of the activity of cytochrome P450 2D6 (CYP2D6), a highly variable drug-metabolizing enzyme, is performed through phenotyping during which a probe drug is administered to measure the enzyme’s activity. In order to avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-invasive tools for real-time phenotyping of CYP2D6 could significantly contribute to the expansion of precision medicine in clinical practice. This study focuses on the identification of endogenous markers of the CYP2D6 enzyme in human biofluids using a liquid chromatography (LC)-high-resolution mass spectrometry (HRMS)-based metabolomics approach. Experimental Approach: Data from a control session were compared to data from an inhibition session. Before the latter, healthy volunteers (extensive and ultrarapid metabolizers) received a daily dose of paroxetine 20 mg over seven days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. Key Results: In CYP2D6 extensive and ultrarapid metabolizers (n = 37), mean relative intensities of five features were significantly reduced during the inhibition session compared to the control session (fold changes ≤ 0.67, FDR-adjusted P < 0.0001). Furthermore, mean relative intensities of these candidates were significantly higher in the CYP2D6 extensive-ultrarapid metabolizer group (n = 37) compared to the poor metabolizer group (n = 6) (fold changes ≤ 0.67, P < 0.0001). Conclusion and Implications: The applied untargeted metabolomics strategy was able to identify five CYP2D6 endogenous metabolites, a promising discovery for non-invasive phenotyping and personalised medicine.

Peer review status:IN REVISION

09 Dec 2020Submitted to British Journal of Pharmacology
09 Dec 2020Assigned to Editor
09 Dec 2020Submission Checks Completed
22 Jan 2021Reviewer(s) Assigned
07 Mar 2021Review(s) Completed, Editorial Evaluation Pending
15 Mar 2021Editorial Decision: Revise Minor