Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway
ObjectivesThe purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.MethodSprague-Dawley rats were randomly divided into two groups: a normal control group and a ceftriaxone-associated dysbiotic gro...
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Frontiers Media S.A.
2025-01-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1522271/full |
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| author | Xiaokang Wang Xiaokang Wang Chunxiao Ye Xixiao Yang Maoxun Yang Maoxun Yang Maoxun Yang |
| author_facet | Xiaokang Wang Xiaokang Wang Chunxiao Ye Xixiao Yang Maoxun Yang Maoxun Yang Maoxun Yang |
| author_sort | Xiaokang Wang |
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| description | ObjectivesThe purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.MethodSprague-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.Key findingsThe 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.ConclusionOMVs 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. |
| format | Article |
| id | doaj-art-25ad83df4d70480ca9dd8bafe449fffc |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-25ad83df4d70480ca9dd8bafe449fffc2025-01-03T05:10:13ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-01-011510.3389/fphar.2024.15222711522271Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathwayXiaokang Wang0Xiaokang Wang1Chunxiao Ye2Xixiao Yang3Maoxun Yang4Maoxun Yang5Maoxun Yang6The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, ChinaDepartment of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, ChinaDepartment of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, ChinaThe Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, ChinaGuangdong Provincial Key Laboratory of Research and Development of Natural Drugs, Guangdong Medical University, Dongguan, ChinaSchool of Pharmacy, Guangdong Medical University, Dongguan, ChinaObjectivesThe purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.MethodSprague-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.Key findingsThe 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.ConclusionOMVs 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.https://www.frontiersin.org/articles/10.3389/fphar.2024.1522271/fullintestinal bacteriaceftriaxonevoriconazolebioavailabilityP-glycoprotein |
| spellingShingle | Xiaokang Wang Xiaokang Wang Chunxiao Ye Xixiao Yang Maoxun Yang Maoxun Yang Maoxun Yang Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway Frontiers in Pharmacology intestinal bacteria ceftriaxone voriconazole bioavailability P-glycoprotein |
| title | Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway |
| title_full | Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway |
| title_fullStr | Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway |
| title_full_unstemmed | Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway |
| title_short | Ceftriaxone-associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal P-glycoprotein expression through activation of the Nrf2-mediated signalling pathway |
| title_sort | ceftriaxone associated dysbiosis decreases voriconazole bioavailability by upregulating intestinal p glycoprotein expression through activation of the nrf2 mediated signalling pathway |
| topic | intestinal bacteria ceftriaxone voriconazole bioavailability P-glycoprotein |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1522271/full |
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