Metabolomics reveals five endogenous biomarkers in human urine and plasma to predict cyp2d6 activity

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_8116E84FC609
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Metabolomics reveals five endogenous biomarkers in human urine and plasma to predict cyp2d6 activity
Journal
British Journal of Pharmacology
Author(s)
Magliocco G., Matthey A., Bararpour N., Joye T., Gloor Y., Desmeules J., Thomas A., Daali Y.
ISSN
0007-1188
Publication state
Published
Issued date
22/01/2021
Peer-reviewed
Oui
Language
english
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.
Keywords
CYP450, phenotyping, metabolomics, CYP2D6, endobiotics
Open Access
Yes
Create date
26/01/2021 8:28
Last modification date
18/02/2021 7:28
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