Impact of Acute Inflammation on Cytochromes P450 Activity Assessed by the Geneva Cocktail

Abstract

Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL-6, IL-1β, TNF-α, and IFN-γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P < 0.0001) between baseline and the nadir at D1. CYP2C19 and CYP3A activities (MRs) decreased by 57% (P = 0.0002) and 61% (P < 0.0001), respectively, with the nadir at D3. CYP2B6 and CYP2C9 MRs increased by 120% (P < 0.0001) and 79% (P = 0.018), respectively, and peaked at D1. Surgery did not have a significant impact on CYP2D6 MR. Hip surgery was a good acute inflammation model as CRP, IL-6, and TNF-α peak levels were reached between D1 and day 2 (D2). Acute inflammation modulated CYP activity in an isoform-specific manner, with different magnitudes and kinetics. Acute inflammation may thus have a clinically relevant impact on the pharmacokinetics of these CYP substrates.

Impact of Inflammation on Cytochromes P450 Activity in Pediatrics: A Systematic Review

“…Another hypothesis is that the CYP2C19 contribution to CYP3A is more affected by inflammation. We have indeed previously demonstrated in adults that CYP3A was more impacted by inflammation than CYP2C19 [104].…”

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

“…Threshold values were the same as those already detailed in our previous cohort study. 11 The MRs of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A were measured twice, i.e., during the first 72 hours of the patient's hospitalization and 3 months after. To assess the phenotype of each CYP of interest, probe substrates contained in the Geneva cocktail (caffeine 50 mg, CYP1A2; bupropion 20 mg, CYP2B6; flurbiprofen 10 mg, CYP2C9; omeprazole 10 mg, CYP2C19; dextromethorphan 10 mg, CYP2D6; midazolam 1 mg, CYP3A; fexofenadine 25 mg, Pglycoprotein) were orally administered and capillary blood samples were collected 2 hours later from a fasting patient, with dried blood spots using a previously validated sampling method.…”

CYP450 Genotype—Phenotype Concordance Using the Geneva Micrococktail in a Clinical Setting

“…Phenotype determination was based on the metabolite to parent drug metabolic ratio (MR). As for genotyping, patients were classified as PM, IM, NM, and UM according to their MR (Lenoir et al, 2020).…”

“…This new formulation of the Geneva cocktail recently showed an excellent safety profile in 265 healthy volunteers from different geographic regions (Rollason et al, 2020b). It was also used to characterize the variation in CYP450 activity in patients undergoing elective orthopedic surgery (Lenoir et al, 2020).…”