Impact of SARS‐CoV‐2 Infection (COVID‐19) on Cytochromes P450 Activity Assessed by the Geneva Cocktail

Abstract

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (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 (CYPs) activity in an isoform-specific manner. We therefore hypothesized that COVID-19 might also impact CYP activity, 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. 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 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factorα (TNFα) levels were also measured in blood. 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 patients with COVID-19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR 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 TNFα were significantly (P < 0.001) higher during SARS-CoV-2 infection. CYP activity 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.

Melatonin effect on platelets and coagulation: Implications for a prophylactic indication in COVID-19

“…The inflammatory status of COVID-19, as well as the release of inflammatory cytokines such as IL-1, IFN, TNFα, and especially IL-6 are associated with decreased activity of drug-metabolizing enzymes and transporters [84] , [87] . As reported, CYP2C19 was associated with the largest decrease in its activity (75 %) after SARS-CoV-2 infection, which inversely associated with the elevation of IL-6, TNF-α, and CRP levels [86] , [88] , [89] . In a cohort study, CYP2C19 activity decreased by 57 % and was found to be negatively correlated with CRP levels [90] .…”

“…The activity of CYP450 is inhibited by inflammation in pre-and post-transcriptional pathways [86] . The inflammatory status of COVID-19, as well as the release of inflammatory cytokines such as IL-1, IFN, TNFα, and especially IL-6 are associated with decreased activity of drug-metabolizing enzymes and transporters [84] , [87] .…”

Physiologically Based Pharmacokinetic Modeling Approaches for Patients With SARS‐CoV‐2 Infection: A Case Study With Imatinib

“…Interestingly, the CYP3A‐mediated hydroxylation of midazolam in patients with moderate to severe SARS‐CoV‐2 infections was reduced only to a minor extent (22%) compared to the baseline value (after recovery from the infection). 39 However, the potential effect of elevated serum IL‐6 level on the pharmacokinetics of other CYP3A substrates and on the activity of other CYP enzymes (ie, CYP1A2 and CYP2C19) in SARS‐CoV‐2 infection should be considered. 39 It is worth mentioning that dexamethasone as an anti‐inflammatory corticosteroid drug may downregulate the production of IL‐6, potentially offsetting its CYP suppression activity.…”

“… 39 However, the potential effect of elevated serum IL‐6 level on the pharmacokinetics of other CYP3A substrates and on the activity of other CYP enzymes (ie, CYP1A2 and CYP2C19) in SARS‐CoV‐2 infection should be considered. 39 It is worth mentioning that dexamethasone as an anti‐inflammatory corticosteroid drug may downregulate the production of IL‐6, potentially offsetting its CYP suppression activity. A complex semimechanistic turnover model may provide further insights into the dynamic interplay between IL‐6 and dexamethasone on net CYP3A activity.…”

COVID-19 infection, fluctuations in the clozapine/norclozapine levels and metabolic ratio and clozapine toxicity: An illustrative case-report

“…Nevertheless, a review of several studies indicated that the clozapine/norclozapine ratio is not a good measure of CYPIA2 activity or of clinical response, but the authors also noted none of reviewed studies assessed a single subject longitudinally with regards to the clozapine/norclozapine ratio ( Schoretsanitis et al, 2019 ). A recent Swiss study assessed SARS-CoV-2 infection's impact on hepatic cytochromes and reported a 53% inhibition of CYP1A2, 23% inhibition of CYP3A and 75% inhibition of 2C19 enzyme activity, all major metabolic pathways for clozapine during the infection with normalization upon resolution ( Lenoir et al, 2021 ).…”