MMSL 2022, 91(88):36

HUMAN PRECISION-CUT INTESTINAL SLICES AS A MODEL TO STUDY DRUG-MEDIATED INDUCTION OF INTESTINAL ABCB1 AND CYP3A4Meeting abstracts

Martin Huličiak, Tereza Hradecká, Tereza Mazurová, Pavla Podhorná, Lukáš Červený, Ivan Vokřál
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, The Czech Republic

Drug-mediated induction of the intestinal ABCB1 and CYP3A4 is a clinically relevant phenomenon associated with reduced drug bioavailability. Well-established human models to assess the induction are currently missing, so drug regulatory authorities provide no recommendations to test in vitro/ex vivo drugs' induction activity. Human precision-cut intestinal slices (hPCIS) contain cells in their natural environment and express physiological levels of nuclear factors required for induction. We recently found that hPCIS incubated for 48 h retained intact morphology, ATP content, and ABCB1 activity. We also confirmed that rifampicin (30 µM) induces gene expression and protein level of the ABCB1 over the 48-h incubation. Here, we aim to evaluate whether model ligands for glucocorticoid receptor (dexamethasone) and vitamin D receptor (vitamin D3) induce ABCB1 and CYP3A4 expression in hPCIS over the 48-h incubation. Moreover, darunavir, a clinically used anti-HIV drug, was evaluated using this model. Dexamethasone (100 µM) increased the CYP3A4 and ABCB1 gene expression significantly after 48-h, 19.68- and 3.00-fold, respectively. Darunavir (50 µM) after 24-h significantly increased CYP3A4 and ABCB1 gene expression 7.42- and 2.07-fold, respectively. Vitamin D3 (100 nM) increased CYP3A4 expression 2.29-fold after 48-h incubation; however, confirmation of inducibility requires multiple repeats. On ABCB1 expression, vitamin D3 had no effect. To conclude, hPCIS is a promising model for investigating drug induction potential. The study was supported by the GAUK 364521 and SVV 260 549.

Keywords: induction; ABCB1; CYP3A4; human precision-cut intestinal slices

Published: June 20, 2022  Show citation

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Huličiak, M., Hradecká, T., Mazurová, T., Podhorná, P., Červený, L., & Vokřál, I. (2022). HUMAN PRECISION-CUT INTESTINAL SLICES AS A MODEL TO STUDY DRUG-MEDIATED INDUCTION OF INTESTINAL ABCB1 AND CYP3A4. MMSL91(Suppl.1), 36
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