impact of acute and chronic inflammation on cytochromes p450 activity measured with dried blood spot

Conditions: Inflammation

Summary: cytochromes p450, main enzymes of drug metabolism, play a prominent role in the first-pass metabolism of oral substances. inter-individual variability in their activity due to genetic and environmental factors has been observed and may be associated with adverse therapeutic outcomes (ineffectiveness or toxicity). the inflammation, whether acute or chronic, can theoretically modulate the pharmacokinetics of drugs by modulating enzyme activity. indeed, in vitro data and animal models, as well as more limited data in humans, indicate a down-regulation of cyp in the context of inflammation. the cocktail approach developed and validated in geneva ("cocktail geneva") measures the activity of several cyp simultaneously using micro-doses of probe drugs and facilitating sampling (10ul capillary blood) on a dried blood spot. we intend to measure the activity of cyp in an acute inflammation model (hip surgery and sars-cov-2 infection) and chronic inflammation (rheumatoid arthritis, ra). the effect of the biological agent tocilizumab (anti il-6 receptor) in a treated patient subgroup (patients treated regardless of our study) will be measured after 3 months of treatment. the main objective is to determine if interleukin 6 levels are correlated with the activity of cyp450 in patients with acute (orthopedic surgery - hip or sars-cov-2 infection) or chronic inflammation (ra). secondary objectives are: * to correlate cyps activities with the levels of other inflammatory markers (crp, tnf-α, il-1β, ifn-γ); * to assess correlation between markers of inflammation, cyp activities and the intensity of fatigue and pain; * to assess if tocilizumab reverse cyp activity in patients with ra after 3 months treatment; * to assess if sars-cov-2 infection modify pharmacokinetic parameters of concomitant medications which are cyps substrates


Eligibility criteria:
--\> inclusion criteria: for hip surgery and chronic inflammation groups * male and female patients diagnosed with rheumatoid arthritis or undergoing an elective hip surgery * age \> 18 years old * understanding of french language and ability to give a written inform consent for sars-cov-2 infection group * male and female patients diagnosed with sars-cov-2 infection (positive rt-pcr) and crp \> 30 mg/l * age \> 18 years old * understanding of french language and ability to give a written inform consent --\> exclusion criteria: for hip surgery and chronic inflammation groups * pregnant or lactating females * severe cardiac failure, severe edema or ascites * severe copd or pulmonary embolism requiring oxygen * uncontrolled infection * active cancer * hiv infection * renal impairment (defined as serum creatinine concentrations \> 1.5 x uln) * hepatic impairment (alteration of hepatic tests ast, alt, bilirubin, ggt \>2 x uln) * inability to give blood samples * sensitivity to any of the drugs used * intake of drugs altering cyps activity (based on \[1\]) except for tocilizumab for sars-cov-2 infection group * pregnant or lactating females * hospitalized in intensive care unit at time of inclusion * hospitalized in intermediate care unit at time of inclusion * active cancer * hiv infection * renal impairment (glomerular filtration rate \< 30 ml/min/1.73m2) * hepatic impairment (child-pugh score b and c) * inability to give blood samples * sensitivity to any of the drugs used

Keywords: cytochromes p450 chronic inflammation genotyping phenotyping acute inflammation rheumatoid arthritis surgery covid-19 sars-cov-2 infection