Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity

Article Article scientifique Article Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity eng 2021-08-07 2021-12 author Magliocco Gaëlle 0000-0003-4352-5440 752117 author Desmeules Jules Alexandre 73542 author Matthey Alain 558446 author Quiros Guerrero Luis Manuel 0000-0002-1630-8697 902707 author Bararpour Nasim 791774 author Joye Timothee 698559 author Marcourt Laurence 729234 author Ferreira Queiroz Emerson 135675 author Wolfender Jean-Luc 135649 author Gloor Yvonne Sylvia 0000-0002-8790-0479 135176 author Thomas Aurélien 647674 author Daali Youssef 46042 4708-4725 10.1111/bph.15651 34363609 0007-1188 PMC9290485 Background and purpose: Individualized assessment of cytochrome P450 2D6 (CYP2D6) activity is usually performed through phenotyping following administration of a probe drug to measure the enzyme's activity. To avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non-burdensome tools for real-time phenotyping of CYP2D6 could significantly contribute to precision medicine. This study focuses on the identification of markers of the CYP2D6 enzyme in human biofluids using an LC-high-resolution mass spectrometry-based metabolomic approach. Experimental approach: Plasma and urine samples from healthy volunteers were analysed before and after intake of a daily dose of paroxetine 20 mg over 7 days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants. Key results: We report four metabolites of solanidine and two unknown compounds as possible novel CYP2D6 markers. Mean relative intensities of these features were significantly reduced during the inhibition session compared with the control session (n = 37). Semi-quantitative analysis showed that the largest decrease (-85%) was observed for the ion m/z 432.3108 normalized to solanidine (m/z 398.3417). Mean relative intensities of these ions were significantly higher in the CYP2D6 normal-ultrarapid metabolizer group (n = 37) compared with the poor metabolizer group (n = 6). Solanidine intensity was more than 15 times higher in CYP2D6-deficient individuals compared with other volunteers. Conclusion and implications: The applied untargeted metabolomic strategy identified potential novel markers capable of semi-quantitatively predicting CYP2D6 activity, a promising discovery for personalized medicine. CYP2D6 CYP450 Biomarker Metabolomics Phenotyping Biomarkers Cytochrome P-450 CYP2D6 / genetics Cytochrome P-450 CYP2D6 / metabolism Humans Metabolomics Phenotype Precision Medicine Cytochrome P-450 CYP2D6 Dewey 615 Dewey 614.1 Dewey 617 Dewey 618 Geneva University Hospitals 31 Section des sciences pharmaceutiques 17 217 Centre de recherche clinique 201 67 Institut de médecine légale 22A2 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 false 1280 Pharmaco-omiques et médecine de précision 1003 302 Groupe Desmeules Jules (pharmacologie/toxicologie) 567 British journal of pharmacology 178 23 4cc28f7b-8d56-4beb-ac8f-6c1e802331d3 Article (Published version) Public British J Pharmacology - 2021 - Mag.pdf 8664145 application/pdf CC BY-NC-ND-4.0 527b0810-4c45-44bd-9717-ee33b79cf9cb Appendix Public bph15651-sup-0001-supporting_inform.docx 4761700 application/vnd.openxmlformats-officedocument.wordprocessingml.document Supplementary tables and figures openAccess Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Centre de recherche clinique Faculté de médecine / Section de médecine clinique / Département de santé et médecine communautaires / Institut de médecine légale Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences

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Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity	British journal of pharmacology			2021	339	335

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Bararpour, Nasim