Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota
Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. The pathogenesis of HN is directly related to urea metabolism in the gut microbiota. Febuxostat, a potent xanthine oxidase inhibitor, is the first-line drug used for the treatment of hyperuricemia. However, there have...
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1031509/full |
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| author | Zhen Xiong Zhao Xiao Hui Tang Sheng Lu Jiang Jia Qian Pang Yu Bin Xu Dan Dan Yuan Ling Ling Zhang Hui Min Liu Qing Fan |
| author_facet | Zhen Xiong Zhao Xiao Hui Tang Sheng Lu Jiang Jia Qian Pang Yu Bin Xu Dan Dan Yuan Ling Ling Zhang Hui Min Liu Qing Fan |
| author_sort | Zhen Xiong Zhao |
| collection | DOAJ |
| description | Hyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. The pathogenesis of HN is directly related to urea metabolism in the gut microbiota. Febuxostat, a potent xanthine oxidase inhibitor, is the first-line drug used for the treatment of hyperuricemia. However, there have been few studies on the pharmacokinetics of febuxostat in HN animal models or in patients. In this study, a high-purine diet-induced HN rat model was established. The pharmacokinetics of febuxostat in HN rats was evaluated using LC-MS/MS. Astragaloside IV (AST) was used to correct the abnormal pharmacokinetics of febuxostat. Gut microbiota diversity analysis was used to evaluate the effect of AST on gut microbiota. The results showed that the delayed elimination of febuxostat caused drug accumulation after multiple administrations. Oral but not i. p. AST improved the pharmacokinetics of febuxostat in HN rats. The mechanistic study showed that AST could regulate urea metabolism in faeces and attenuate urea-ammonia liver-intestine circulation. Urease-related genera, including Eubacterium, Parabacteroides, Ruminococcus, and Clostridia, decreased after AST prevention. In addition, the decrease in pathogenic genera and increase in short-chain fatty acids (SCFA) producing genera also contribute to renal function recovery. In summary, AST improved the pharmacokinetics of febuxostat in HN rats by comprehensive regulation of the gut microbiota, including urea metabolism, anti-calcification, and short-chain fatty acid generation. These results imply that febuxostat might accumulate in HN patients, and AST could reverse the accumulation through gut microbiota regulation. |
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| language | English |
| last_indexed | 2024-04-13T04:18:13Z |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-1045029dbe414ecf8136a903c60217512022-12-22T03:02:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10315091031509Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiotaZhen Xiong Zhao0Xiao Hui Tang1Sheng Lu Jiang2Jia Qian Pang3Yu Bin Xu4Dan Dan Yuan5Ling Ling Zhang6Hui Min Liu7Qing Fan8Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, ChinaShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, ChinaTaizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, ChinaTaizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, ChinaTaizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, ChinaShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, ChinaTaizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, ChinaShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, ChinaShandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, ChinaHyperuricemic nephropathy (HN) is a common clinical complication of hyperuricemia. The pathogenesis of HN is directly related to urea metabolism in the gut microbiota. Febuxostat, a potent xanthine oxidase inhibitor, is the first-line drug used for the treatment of hyperuricemia. However, there have been few studies on the pharmacokinetics of febuxostat in HN animal models or in patients. In this study, a high-purine diet-induced HN rat model was established. The pharmacokinetics of febuxostat in HN rats was evaluated using LC-MS/MS. Astragaloside IV (AST) was used to correct the abnormal pharmacokinetics of febuxostat. Gut microbiota diversity analysis was used to evaluate the effect of AST on gut microbiota. The results showed that the delayed elimination of febuxostat caused drug accumulation after multiple administrations. Oral but not i. p. AST improved the pharmacokinetics of febuxostat in HN rats. The mechanistic study showed that AST could regulate urea metabolism in faeces and attenuate urea-ammonia liver-intestine circulation. Urease-related genera, including Eubacterium, Parabacteroides, Ruminococcus, and Clostridia, decreased after AST prevention. In addition, the decrease in pathogenic genera and increase in short-chain fatty acids (SCFA) producing genera also contribute to renal function recovery. In summary, AST improved the pharmacokinetics of febuxostat in HN rats by comprehensive regulation of the gut microbiota, including urea metabolism, anti-calcification, and short-chain fatty acid generation. These results imply that febuxostat might accumulate in HN patients, and AST could reverse the accumulation through gut microbiota regulation.https://www.frontiersin.org/articles/10.3389/fphar.2022.1031509/fullhyperuricemic nephropathygut microbiotafebuxostatastragaloside IVuric acid |
| spellingShingle | Zhen Xiong Zhao Xiao Hui Tang Sheng Lu Jiang Jia Qian Pang Yu Bin Xu Dan Dan Yuan Ling Ling Zhang Hui Min Liu Qing Fan Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota Frontiers in Pharmacology hyperuricemic nephropathy gut microbiota febuxostat astragaloside IV uric acid |
| title | Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota |
| title_full | Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota |
| title_fullStr | Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota |
| title_full_unstemmed | Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota |
| title_short | Astragaloside IV improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota |
| title_sort | astragaloside iv improves the pharmacokinetics of febuxostat in rats with hyperuricemic nephropathy by regulating urea metabolism in gut microbiota |
| topic | hyperuricemic nephropathy gut microbiota febuxostat astragaloside IV uric acid |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1031509/full |
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