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

Magliocco, Gaëlle; Desmeules, Jules Alexandre; Matthey, Alain; Quirós-Guerrero, Luis; Bararpour, Nasim; Joye, Timothée; Marcourt, Laurence; Queiroz, Emerson Ferreira; Wolfender, Jean‐Luc; Gloor, Yvonne; Thomas, Aurélien; Daali, Youssef

doi:10.1111/bph.15651

Cited by 22 publications

(37 citation statements)

References 61 publications

(99 reference statements)

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“…For methods which acquire non-selective full-scan HRMS data, these data can be retrospectively reprocessed for compounds that were not targeted in the initial analysis, without the need of re-extraction and re-analysis of the sample. Solanidine and five solanidine metabolites (M412, M414, M416, M432, and M444), which were recently described by Magliocco et al [ 11 ], were identified in the HRMS data files by accurate mass (the protonated molecular ion was present within a mass tolerance of 5 ppm) and isotope ratio. The MS/MS spectrums of the identified peaks, acquired using the full-scan ddMS2 mode, all showed a major fragment at m/z 98.0967, which further confirmed detection of the same solanidine metabolites as described previously [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…Solanidine and five solanidine metabolites (M412, M414, M416, M432, and M444), which were recently described by Magliocco et al [ 11 ], were identified in the HRMS data files by accurate mass (the protonated molecular ion was present within a mass tolerance of 5 ppm) and isotope ratio. The MS/MS spectrums of the identified peaks, acquired using the full-scan ddMS2 mode, all showed a major fragment at m/z 98.0967, which further confirmed detection of the same solanidine metabolites as described previously [ 11 ]. The same MS/MS fragmentation pattern was also evident for two additional peaks, M402 and M440, which were discovered by use of the metabolomics software Compound Discoverer 3.2 (Thermo Fisher Scientific, Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, Magliocco et al performed a non-targeted metabolomics study and reported that solanidine and its metabolites may have potential as CYP2D6 biomarkers [ 11 ]. Their evidence was based on the fact that plasma levels of solanidine metabolites decreased significantly during use of the potent CYP2D6 inhibitor paroxetine, as well as lower metabolite levels occurring in CYP2D6 poor versus normal-ultrarapid metabolizers.…”

Section: Introductionmentioning

confidence: 99%

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Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype

Wollmann

Størset

Kringen

et al. 2023

Eur J Clin Pharmacol

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Purpose Poor metabolizers (PMs) of the highly polymorphic enzyme CYP2D6 are usually at high risk of adverse effects during standard recommended dosing of CYP2D6-metabolized drugs. We studied if the metabolism of solanidine, a dietary compound found in potatoes, could serve as a biomarker predicting the CYP2D6 PM phenotype for precision dosing. Methods The study included 839 CYP2D6-genotyped patients who were randomized by a 4:1 ratio into test or validation cohorts. Full-scan high-resolution mass spectrometry data files of previously analyzed serum samples were reprocessed for identification and quantification of solanidine and seven metabolites. Metabolite-to-solanidine ratios (MRs) of the various solanidine metabolites were calculated prior to performing receiver operator characteristic (ROC) and multiple linear regression analyses on the test cohort. The MR thresholds obtained from the ROC analyses were tested for the prediction of CYP2D6 PMs in the validation cohort. Results In the test cohort, the M414-to-solanidine MR attained the highest sensitivity and specificity parameters from the ROC analyses (0.98 and 1.00) and highest explained variance from the linear models (R2 = 0.68). Below these thresholds, CYP2D6 PM predictions were tested in the validation cohort providing positive and negative predictive values of 100% for the MR of M414, while similar values for the other MRs ranged from 20.5 to 73.3% and 96.7 to 99.3%, respectively. Conclusion The M414-to-solanidine MR is an excellent predictor of the CYP2D6 PM phenotype. By measuring solanidine and metabolites using liquid chromatography-mass spectrometry in patient serum samples, CYP2D6 PMs can easily be identified, hence facilitating the implementation of precision dosing in clinical practice.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype

Wollmann

Størset

Kringen

et al. 2023

Eur J Clin Pharmacol

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show abstract

“…Numerous drugs are metabolized by an isoenzyme family called cytochrome P450 (CYP), which is mostly found in the endoplasmic reticulum of liver cells [ 84 ]. About 25% of all medications used in clinical practice are metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme [ 119 ]. The drug-metabolizing enzyme Cytochrome P450 2D6 (CYP2D6) is produced by the CYP2D6 gene [ 152 ].…”

Section: Control Challengesmentioning

confidence: 99%

Plasmodium vivax: the potential obstacles it presents to malaria elimination and eradication

Habtamu

Petros

Yan

2022

Trop Dis Travel Med Vaccines

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Initiatives to eradicate malaria have a good impact on P. falciparum malaria worldwide. P. vivax, however, still presents significant difficulties. This is due to its unique biological traits, which, in comparison to P. falciparum, pose serious challenges for malaria elimination approaches. P. vivax's numerous distinctive characteristics and its ability to live for weeks to years in liver cells in its hypnozoite form, which may elude the human immune system and blood-stage therapy and offer protection during mosquito-free seasons. Many malaria patients are not fully treated because of contraindications to primaquine use in pregnant and nursing women and are still vulnerable to P. vivax relapses, although there are medications that could radical cure P. vivax. Additionally, due to CYP2D6's highly variable genetic polymorphism, the pharmacokinetics of primaquine may be impacted. Due to their inability to metabolize PQ, some CYP2D6 polymorphism alleles can cause patients to not respond to treatment. Tafenoquine offers a radical treatment in a single dose that overcomes the potentially serious problem of poor adherence to daily primaquine. Despite this benefit, hemolysis of the early erythrocytes continues in individuals with G6PD deficiency until all susceptible cells have been eliminated. Field techniques such as microscopy or rapid diagnostic tests (RDTs) miss the large number of submicroscopic and/or asymptomatic infections brought on by reticulocyte tropism and the low parasitemia levels that accompany it. Moreover, P. vivax gametocytes grow more quickly and are much more prevalent in the bloodstream. P. vivax populations also have a great deal of genetic variation throughout their genome, which ensures evolutionary fitness and boosts adaptation potential. Furthermore, P. vivax fully develops in the mosquito faster than P. falciparum. These characteristics contribute to parasite reservoirs in the human population and facilitate faster transmission. Overall, no genuine chance of eradication is predicted in the next few years unless new tools for lowering malaria transmission are developed (i.e., malaria elimination and eradication). The challenging characteristics of P. vivax that impede the elimination and eradication of malaria are thus discussed in this article.

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“…7 In the field of personalized medicine, there is considerable interest in endogenous compounds metabolized through drug-metabolizing enzymes. 8,9 Indeed, CYP450 enzymes are subject to high intra-and interindividual variability, requiring effective and nonburdensome tools to characterize their activity in a given subject at a specific time. 10 The use of endogenous markers offers numerous advantages over exogenous probes to phenotype CYP450 activity.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of CYP1A2 activity: Relationship between the endogenous urinary 6‐hydroxymelatonin to melatonin ratio and paraxanthine to caffeine ratio in dried blood spots

Magliocco

Desmeules

Samer

et al. 2022

Clinical Translational Sci

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

Abstract: conceived and designed the clinical trial. G.M, J.D. and A.M. performed the clinical trial. G.M. and Y.G. performed CYP2D6 genotyping. G.M., N.B., T.J. and A.T. performed metabolomic analyses.

Cited by 22 publications

References 61 publications

Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype

Prediction of CYP2D6 poor metabolizers by measurements of solanidine and metabolites—a study in 839 patients with known CYP2D6 genotype

Plasmodium vivax: the potential obstacles it presents to malaria elimination and eradication

Evaluation of CYP1A2 activity: Relationship between the endogenous urinary 6‐hydroxymelatonin to melatonin ratio and paraxanthine to caffeine ratio in dried blood spots

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