Skip to main content

ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Drug Metabolism and Transport
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1522271
This article is part of the Research Topic Drug Metabolism and Transport: The Frontier of Personalized Medicine Volume II View all 17 articles

Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway

Provisionally accepted
Xiaokang Wang Xiaokang Wang 1*Chunxiao Ye Chunxiao Ye 2Maoxun Yang Maoxun Yang 1
  • 1 Guangdong Provincial Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China
  • 2 The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China

The final, formatted version of the article will be published soon.

    Objectives The purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.Method Sprague-Dawley rats were randomly divided into two groups: a normal control group and a ceftriaxone-associated dysbiotic group. The composition of the intestinal flora was examined using 16S rRNA sequencing analysis. Voriconazole concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Outer membrane vesicles (OMVs) of microbes from the different groups were prepared for in vitro study in Caco-2 cells. The Nrf2 pathway and its related proteins involved in modifying P-glycoprotein (P-gp) expression were clarified by a series of immunoblot analyses.The diversity and richness of intestinal bacteria, especially the abundance of gram-negative bacteria, were significantly decreased after ceftriaxone treatment. The AUC(0-t) and Cmax of voriconazole were reduced, and greater voriconazole clearance were noted in the dysbiotic group. An in vivo study also indicated that the expression of P-glycoprotein was significantly increased after ceftriaxone treatment, which may be due to the absence of gram-negative bacteria in the intestine. Finally, in vitro findings in Caco-2 cells treated with OMVs from the ceftriaxone-associated dysbiotic group suggested that Nrf2 translocation into the nucleus induced high expression of P-gp.Conclusions OMVs from intestinal bacterial in the ceftriaxone-associated dysbiotic group induced high P-gp expression by regulating the Nrf2 signalling pathway, which led to an in vivo reduction in the bioavailability of voriconazole due to ceftriaxone-associated dysbiosis.

    Keywords: Intestinal bacteria, Ceftriaxone, Voriconazole, bioavailability, Pglycoprotein

    Received: 04 Nov 2024; Accepted: 05 Dec 2024.

    Copyright: © 2024 Wang, Ye and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Xiaokang Wang, Guangdong Provincial Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.