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降尿酸化合物的活性评价方法研究进展

祁丹辉, 史晓雨, 刘新泳, 展鹏

祁丹辉,史晓雨,刘新泳,等. 降尿酸化合物的活性评价方法研究进展[J]. 中国药科大学学报,2024,55(2):167 − 180. DOI: 10.11665/j.issn.1000-5048.2023080103
引用本文: 祁丹辉,史晓雨,刘新泳,等. 降尿酸化合物的活性评价方法研究进展[J]. 中国药科大学学报,2024,55(2):167 − 180. DOI: 10.11665/j.issn.1000-5048.2023080103
QI Danhui, SHI Xiaoyu, LIU Xinyong, et al. Recent advances in bioactivity evaluation methods of uric acid-lowering compounds[J]. J China Pharm Univ, 2024, 55(2): 167 − 180. DOI: 10.11665/j.issn.1000-5048.2023080103
Citation: QI Danhui, SHI Xiaoyu, LIU Xinyong, et al. Recent advances in bioactivity evaluation methods of uric acid-lowering compounds[J]. J China Pharm Univ, 2024, 55(2): 167 − 180. DOI: 10.11665/j.issn.1000-5048.2023080103

降尿酸化合物的活性评价方法研究进展

基金项目: 山东省杰出青年科学基金项目(No. ZR2020JQ31)
详细信息
    通讯作者:

    刘新泳: Tel:086-531-88380270 E-mail:xinyongl@sdu.edu.cn

    展鹏: Tel:13793130595   E-mail:zhanpeng1982@sdu.edu.cn

  • 中图分类号: TQ460

Recent advances in bioactivity evaluation methods of uric acid-lowering compounds

Funds: This study was supported by Science Foundation for Outstanding Young Scholars of Shandong Province (No. ZR2020JQ31)
  • 摘要:

    高尿酸血症(hyperuricemia,HUA)是由于体内尿酸升高所导致的一种代谢性疾病,与心血管疾病、代谢紊乱和肾脏并发症风险升高密切相关。活性评价是降尿酸药物研发至关重要的环节。目前,降尿酸药物的活性筛选方法大致分为体外和体内两种,体外筛选主要是基于黄嘌呤氧化酶、尿酸转运蛋白、嘌呤核苷磷酸化酶等靶点建立模型,而体内降尿酸筛选则通过啮齿类、禽类动物及类器官等模型实现。因此,从体内、体外两个方面全面综述了降尿酸化合物的活性评价方法,旨在为降尿酸药物的研发提供信息。

    Abstract:

    Hyperuricemia is a metabolic disease caused by elevated uric acid in the body, and is closely related to the increased risk of cardiovascular disease, metabolic disorders, and renal complications. In the development process of uric acid-lowering drugs, activity evaluation is a crucial step. At present, the activity screening methods of uric acid-lowering drugs can be roughly divided into two categories: in vitro and in vivo. In vitro screening is mainly for such targets as xanthine oxidase, urate transporters, and purine nucleoside phosphorylase, etc.; while in vivo screening is achieved by rodent, poultry and organoid models. In this article, the activity evaluation methods for uric acid-lowering compounds are comprehensively summarized both in vitro and in vivo, aiming to provide some insight for the development of uric acid-lowering drugs.

  • Figure  1.   Diagram of uric acid formation(A) and excretion process(B)PNP: Purine nucleoside phosphorylase; ADA: Adenosine deaminase; XOD:Xanthine oxidase; ABCG2: ATP-binding cassette superfamily G member 2; GLUT9: Glucose transporter 9; OAT1: Organicanion transporter 1; OAT2: Organicanion transporter 2; OAT3: Organicanion transporter 3; URAT1: Urate transporter 1

    Figure  2.   Structures of the approved antigout drugs and representative compounds

    Figure  3.   Catalytic mechanism of xanthine oxidase XOD:Xanthine oxidase inhibitor

    Figure  4.   HPLC analysis of lysate of HK-2 cells treated with adenosine

    Figure  5.   HEK293T cell system expressing human urate transporter 1(hURAT1) protein was constructed by gene transfection

    Figure  6.   Schematic representation of the experimental protocol of patchlamp experiments

    Figure  7.   Procedures of ATP-binding cassette superfamily G member 2(ABCG2) membrane vesicle preparationand inhibitor screening

    Table  1   Modeling method of hyperuricemia(HUA) and other metabolic syndrome in mice

    Medicine and dose Period Method Type Reference
    250 mg/kg Uric acid 10 min ip Acute HUA [48]
    75 mg/kg Adenine 28 d ig HUA [49]
    250 mg/kg Postassium oxonate+150 mg/kg Hypoxanthine 7 d sc+ip HUA [50]
    50 mg/kg Adenine+200 mg/kg Postassium oxonate 21 d po HUA and kidney injury [51]
    300 mg/kg Postassium oxonate 14 d ip HUA and kidney injury [52]
    300 mg/kg Postassium oxonate+300 mg/kg Hypoxanthine 10 d ip HUA in acute kidney disease [53]
    400 mg/kg Postassium oxonate+600 mg/kg Hypoxanthine 4 h sc+ig Acute HUA [26]
    下载: 导出CSV

    Table  2   Modeling method of hyperuricemia and other metabolic syndrome in rats

    Medicine and dose Period Method Type Reference
    600 mg/kg Adenine 5 d po HUA and acute renal failure [62]
    750 mg/kg Postassium oxonate+20% Yeast extract paste 21 d ig HUA [63]
    100 mg/kg Adenine+1500 mg/kg Postassium oxonate 28 d ig HUA nephropathy [64]
    250 mg/kg Ethambutol+200 mg/kg Adenine 28 d ig+sc HUA and kidney injury [65]
    300 mg/kg Postassium oxonate+300 mg/kg Pyrazinamide 7 d sc+ip HUA with poor uric acid excretion [66]
    250 mg/kg Postassium oxonate+250 mg/kg Ethambutol 42 d sc+ig Chronic HUA [67]
    100 mg/kg Adenine+1500 mg/kg Postassium oxonate 35 d ig Chronic HUA and kidney injury [68]
    High-fat diet+High-purine diet+50 mg/kg Adenine+100 mg/kg Potassium bisulfate 28 d po+sc HUA causes atherosclerosis [69]
    Postassium oxonate+2% NaCl 49 d po HUA and hypertension [70]
    10% Fructose+10% Postassium oxonate 98 d ig+sc HUA and kidney injury [71]
    High-fat diet+High-glucose diet+275 mg/kg Postassium oxonate 28 d+28 d po+ip HUA and diabetes [72]
    下载: 导出CSV
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  • 收稿日期:  2023-07-31
  • 刊出日期:  2024-04-24

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