Wang Xiaokang, Ye Chunxiao, Yang Xixiao, Yang Maoxun
The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, China.
Department of Pharmacy, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Front Pharmacol. 2025 Jan 3;15:1522271. doi: 10.3389/fphar.2024.1522271. eCollection 2024.
The purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.
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 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 C of voriconazole were reduced, and greater voriconazole clearance were noted in the dysbiotic group. An 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, 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.
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 reduction in the bioavailability of voriconazole due to ceftriaxone-associated dysbiosis.
本研究旨在探讨肠道菌群失调对伏立康唑生物利用度的影响，并探索其潜在机制。
将Sprague-Dawley大鼠随机分为两组：正常对照组和头孢曲松相关的菌群失调组。采用16S rRNA测序分析检测肠道菌群的组成。通过高效液相色谱-串联质谱法测定伏立康唑浓度。制备不同组微生物的外膜囊泡（OMV）用于在Caco-2细胞中进行研究。通过一系列免疫印迹分析阐明参与调节P-糖蛋白（P-gp）表达的Nrf2途径及其相关蛋白。
头孢曲松治疗后，肠道细菌的多样性和丰富度，尤其是革兰氏阴性菌的丰度显著降低。伏立康唑的AUC(0-t)和C降低，菌群失调组的伏立康唑清除率更高。一项研究还表明，头孢曲松治疗后P-糖蛋白的表达显著增加，这可能是由于肠道中缺乏革兰氏阴性菌所致。最后，用头孢曲松相关的菌群失调组的OMV处理Caco-2细胞的结果表明，Nrf2易位至细胞核诱导了P-gp的高表达。
头孢曲松相关的菌群失调组肠道细菌的OMV通过调节Nrf2信号通路诱导P-gp高表达，这导致头孢曲松相关的菌群失调使伏立康唑的生物利用度降低。
