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Impact of Interleukin-6 on Drug-Metabolizing Enzymes and Transporters in Intestinal Cells

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Abstract

Inflammatory response is characterized by an increase of several cytokines. Some are known to modify drugs pharmacokinetic by reducing the expression levels of drug-metabolizing enzymes (DMEs) and transporters. This impact of inflammatory signaling is well established in hepatic cells, but not in intestinal cells. EpiIntestinal is a 3D human small intestinal tissue model with epithelial polarity, allowing good evaluation of metabolism and drug transport. This study aimed to analyze the effect of IL-6 on this tissue model. RNA sequencing was performed in cells incubated with 5, 10, or 20 ng/mL IL-6 for 8 h to 72 h to study the impact of IL-6 on drug metabolism and pharmacokinetics gene expression. The influence of IL-6 on the activity of cytochromes P450 (CYPs) was studied by measuring metabolite formation of specific substrates with LC-HRMS. Its impact on ATP-binding cassette (ABC) transport was evaluated by measuring intra- and extracellular substrates using spectrofluorometry. Exposure of EpiIntestinal cells to IL-6 resulted in reduction of some CYP mRNAs, such as CYP2C19, CYP2C9, and CYP3A4, by 40% to 50%. Activities of these CYPs were also decreased in EpiIntestinal cells by 20% to > 75%. IL-6 exposure did not modify ABCB1 and ABCCs transporter activities in this model. This study shows that gene expression levels and activities of drug-metabolizing enzymes and ABC transporters may be altered by the pro-inflammatory cytokine IL-6 in intestinal cells. If these results are confirmed in vivo, it may result in pharmacokinetic modifications, such as pre-systemic metabolism, with clinical effects, and require dosage adaptation.

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Funding

This work was supported by Institut de Recherches Internationales Servier.

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Authors and Affiliations

  1. EA3738, Faculté de médecine de Lyon-Sud, Université de Lyon 1, Oullins, France

    Florian Simon & Michel Tod

  2. Laboratoire de biochimie-toxicologie, Centre hospitalier Lyon-Sud, Hospices civils de Lyon, Pierre Bénite, Lyon, France

    Florian Simon, Jessica Garcia, Laetitia Guyot, Jérôme Guitton & Léa Payen

  3. Department of biostatistics, Hospices Civils de Lyon, Lyon, France

    Gaelle Vilchez & Claire Bardel

  4. Institut de recherches internationales Servier, Suresnes, France

    Florian Simon & Marylore Chenel

Authors
  1. Florian Simon
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  2. Jessica Garcia
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  3. Laetitia Guyot
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  4. Jérôme Guitton
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  5. Gaelle Vilchez
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  6. Claire Bardel
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  7. Marylore Chenel
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  8. Michel Tod
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  9. Léa Payen
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Contributions

Participated in research design: Payen, Tod, Chenel

Conducted experiments: Simon, Garcia, Guyot, Guitton

Performed data analysis: Simon, Vilchez, Bardel

Wrote or contributed to the writing of the manuscript: Simon, Tod, Payen, Chenel

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Correspondence to Florian Simon.

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Simon, F., Garcia, J., Guyot, L. et al. Impact of Interleukin-6 on Drug-Metabolizing Enzymes and Transporters in Intestinal Cells. AAPS J 22, 16 (2020). https://doi.org/10.1208/s12248-019-0395-x

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