Metabolomic approaches for the discovery of new biomarkers of cytochromes P450 activity

Cytochromes P450 (CYP) are responsible for a large part of the metabolism of drugs and other xenobiotics. Their enzymatic activities vary considerably from one individual to another depending on a combination of intrinsic and environmental factors and resulting in an important inter-individual response to drug treatment. The consequences of this variability are regularly observed in routine clinical practice, affecting both treatment efficacy and the occurrence of adverse effects. All current CYP phenotyping methods rely on the administration of exogenous probes, which excludes vulnerable patients (pregnant women, children, frail or allergic patients) and precludes retrospective studies in biobank samples.

The goal of the project is the development of non-burdensome CYP activity prediction tools using endogenous biomarkers instead of probe drugs. For that matter, the identification of new CYP biomarkers using untargeted metabolomics in plasma, urine and liver-derived extracellular vesicles from healthy volunteers, considering genotype, phenotype, and modulation of CYP activities in the presence of CYP inhibitors or inducers will be performed.

Potential candidate biomarkers will be investigated and a first step real-life validation will be performed by testing the obtained markers in a patient cohort to contribute to the development of personalized therapies and to improve the clinical treatment options for patients.