Background and purpose Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2 infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We have previously demonstrated that acute inflammation modulates cytochromes P450 (CYP) activities in an isoform-specific manner. We therefore hypothesized that COVID-19 might also impact CYP activities, and thus aimed to evaluate the impact of acute inflammation in the context of SARS-CoV-2 infection on the six main human CYPs activity. Experimental Approach This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID-19. They received the Geneva phenotyping cocktail orally during the first 72h of hospitalization and after three months. Capillary blood samples were collected 2h after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A. CRP, IL-6 and TNF-α levels were also measured in blood. Key Results CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (p=0.0001), 74.7% (p=0.0006) and 22.8% (p=0.045), respectively, in COVID-19 patients. CYP2B6 and CYP2C9 MRs increased by 101.1% (p=0.009) and 55.8% (p=0.0006) respectively. CYP2D6 MRs variation did not reach statistical significance (p=0.072). As expected, COVID-19 was a good acute inflammation model as mean serum levels of CRP, IL-6 and TNF-α were significantly (p<0.001) higher during SARS-CoV-2 infection. Conclusion and implications CYP activities are modulated in an isoform-specific manner by SARS-CoV-2 infection. The pharmacokinetics of CYP substrates, whether used to treat the disease or as the usual treatment of patients, could be therefore clinically impacted.

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.