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

Abstract

Coronavirus disease 2019 (COVID-19), 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 factor-α (TNF-α) 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 TNF-α 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.

Figure 1

Serum levels of the three inflammatory markers (a) CRP, (b) IL‐6, and (c) TNF‐α during and 3 months after SARS‐CoV‐2 infection (n = 28). The boundary of the box closest to zero indicates the 25^th percentile, the black line within the box marks the median, the cross within the box marks the mean, and the boundary of the box farthest from zero indicates the 75^th percentile. Whiskers above and below the box indicate the 10^th and 90^th percentiles. Points above and below the whiskers indicate outliers. CRP, C‐reactive protein; IL‐6, interleukin 6; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; TNF‐ α, tumor necrosis factor‐α. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Percentage of patients (n = 28) with CYP phenotypic switch between 3 months after (baseline) and during SARS‐CoV‐2 infection: (a) CYP1A2, (b) CYP2C19, (c) CYP3A, (d) CYP2B6, (e) CYP2C9, and (f) CYP2D6. CYP, cytochrome P450; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2. [Colour figure can be viewed at wileyonlinelibrary.com]