Rifampicin and its derivatives: stability, disposition, and affinity towards pregnane X receptor employing 2D and 3D primary human hepatocytes.

Autor: Smutny T; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czech Republic. Electronic address: smutt6aa@faf.cuni.cz., Smutna L; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czech Republic., Lochman L; Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czech Republic. Electronic address: lochmanl@faf.cuni.cz., Kamaraj R; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czech Republic. Electronic address: kamarajr@faf.cuni.cz., Kucera R; Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czech Republic., Pavek P; Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Akademika Heyrovskeho 1203, 500 03 Hradec Kralove, Czech Republic. Electronic address: pavek@faf.cuni.cz.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Nov; Vol. 229, pp. 116500. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1016/j.bcp.2024.116500
Abstrakt: Rifampicin is a model ligand of the pregnane X receptor (PXR), the nuclear receptor involved in the regulation of cytochrome P450 3A4 (CYP3A4). Rifampicin forms several degradation products and metabolites of which 25-desacetylrifampicin is the most abundant in vivo. Here, we aimed to study both the stability and metabolism of rifampicin in media and 2D and 3D primary human hepatocytes (PHHs). Additionally, we analyzed interactions of rifampicin derivatives with PXR. We described that rifampicin gradually degrades by more than 50 % in the medium partly into quinone over 72 h. We observed 25-desacetylrifampicin in 2D PHHs but not in 3D PHHs. Contrary, rifampicin was converted into quinone in a one-direction process in media of 3D PHHs. The potency of rifampicin and its derivatives to activate human PXR was arranged as follows: 3-formylrifamycin SV > rifampicin quinone > rifampicin > rifampicin N-oxide > 25-desacetylrifampicin, respectively, but none activates mouse and rat PXR. The binding differences between rifampicin and 25-desacetylrifampicin were modeled in silico. Finally, we showed that overexpressed uptake organic anion transporting polypeptide 1B1 (OATP1B1) potentiated activation of PXR by rifampicin and rifampicin quinone, but overexpressed efflux multidrug resistance protein 1 (MDR1) decreased PXR activation by all derivatives.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomas Smutny reports financial support was provided by Czech Science Foundation. Tomas Smutny reports financial support was provided by Ministry of Education Youth and Sports of the Czech Republic. Petr Pavek reports financial support was provided by Czech Science Foundation. Petr Pavek reports financial support was provided by Ministry of Education Youth and Sports of the Czech Republic. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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