Wang Xiaokang, Ye Chunxiao, Xun Tianrong, Mo Liqian, Tong Yong, Ni Wensi, Huang Suping, Liu Bin, Zhan Xia, Yang Xixiao
Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
Front Pharmacol. 2021 Apr 15;12:663325. doi: 10.3389/fphar.2021.663325. eCollection 2021.
The antifungal agent voriconazole (VRC) exhibits extreme inter-individual and intra-individual variation in terms of its clinical efficacy and toxicity. Inflammation, as reflected by C-reactive protein (CRP) concentrations, significantly affects the metabolic ratio and trough concentrations of voriconazole. () is an important component of the human intestinal microbiota. Clinical data have shown that abundance is comparatively higher in patients not presenting with adverse drug reactions, and inflammatory cytokine (IL-1β) levels are negatively correlated with abundance. natural product capsular polysaccharide A (PSA) prevents various inflammatory disorders. We tested the hypothesis that PSA ameliorates abnormal voriconazole metabolism by inhibiting inflammation. Germ-free animals were administered PSA intragastrically for 5 days after lipopolysaccharide (LPS) stimulation. Their blood and liver tissues were collected to measure VRC concentrations. PSA administration dramatically improved the resolution phase of LPS-induced hepatic VRC metabolism and inflammatory factor secretion. It reversed inflammatory lesions and alleviated hepatic pro-inflammatory factor secretion. Both and data demonstrate that PSA reversed LPS-induced IL-1β secretion, downregulated the TLR4/NF-κB signaling pathway and upregulated CYP2C19 and P-gp. To the best of our knowledge, this study is the first to show that PSA from the probiotic ameliorates abnormal voriconazole metabolism by inhibiting TLR4-mediated NF-κB transcription and regulating drug metabolizing enzyme and transporter expression. Thus, PSA could serve as a clinical adjunct therapy.
抗真菌药物伏立康唑（VRC）在临床疗效和毒性方面表现出极大的个体间和个体内差异。如C反应蛋白（CRP）浓度所反映的炎症，会显著影响伏立康唑的代谢率和谷浓度。（）是人类肠道微生物群的重要组成部分。临床数据表明，在未出现药物不良反应的患者中，（）的丰度相对较高，且炎性细胞因子（IL-1β）水平与（）丰度呈负相关。益生菌的天然产物荚膜多糖A（PSA）可预防各种炎症性疾病。我们检验了PSA通过抑制炎症来改善伏立康唑代谢异常这一假设。在脂多糖（LPS）刺激后，对无菌动物进行为期5天的PSA灌胃给药。收集它们的血液和肝脏组织以测量VRC浓度。给予PSA显著改善了LPS诱导的肝脏VRC代谢和炎性因子分泌的消退阶段。它逆转了炎性病变并减轻了肝脏促炎因子的分泌。（）和（）数据均表明，PSA逆转了LPS诱导的IL-1β分泌，下调了TLR4/NF-κB信号通路，并上调了CYP2C19和P-糖蛋白。据我们所知，本研究首次表明，来自益生菌（）的PSA通过抑制TLR4介导的NF-κB转录并调节药物代谢酶和转运蛋白的表达来改善伏立康唑代谢异常。因此，PSA可作为一种临床辅助治疗方法。
