Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease-drug interaction of Sarilumab and simvastatin in patients with rheumatoid arthritis. Lee EB, Daskalakis N, Xu C, Paccaly A, Miller B, Fleischmann R, et al. Impact of Interleukin-6 on drug-metabolizing enzymes and transporters in intestinal cells. Simon F, Garcia J, Guyot L, Guitton J, Vilchez G, Bardel C, et al. Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. 2015 43(2):273–83.ĭickmann LJ, Patel SK, Rock DA, Wienkers LC, Slatter JG. A systematic comparison of the impact of inflammatory signaling on absorption, distribution, metabolism, and excretion gene expression and activity in primary human hepatocytes and HepaRG cells. Klein M, Thomas M, Hofmann U, Seehofer D, Damm G, Zanger UM. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Robak T, Gladalska A, Stepien H, Robak E. Cytokine levels (IL-6 and IFN-gamma), acute phase response and nutritional status as prognostic factors in lung cancer.
Martin F, Santolaria F, Batista N, Milena A, Gonzalez-Reimers E, Brito MJ, et al. Role of inflammatory cytokine signaling in the regulation of detoxifying functiuns in human hepatocytes and liver. Inflammation is a major regulator of drug metabolizing enzymes and transporters: consequences for the personalization of drug treatment. Stanke-Labesque F, Gautier-Veyret E, Chhun S, Guilhaumou R. These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration. ResultsĬhanges in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models. After incorporating the respective relationships, we compared the predictions and observed drug concentrations. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. Finally, clinical data on omeprazole were used to validate the findings. The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP).
In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP).
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