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中国防痨杂志 ›› 2025, Vol. 47 ›› Issue (2): 142-149.doi: 10.19982/j.issn.1000-6621.20240483

• 论著 • 上一篇    下一篇

新型化合物舒达吡啶与克拉霉素药物代谢相互作用机制研究

李琦, 王宇津, 王雪钰, 初乃惠(), 聂文娟()   

  1. 首都医科大学附属北京胸科医院结核一科,北京 101149
  • 收稿日期:2024-11-04 出版日期:2025-02-10 发布日期:2025-02-08
  • 通信作者: 聂文娟,Email:xiaobingxiaomei@sina.cn;初乃惠,Email:chunaihui1994@sina.com
  • 基金资助:
    国家自然科学基金(82100002)

Study on the metabolic interaction mechanism between the novel compound WX-081 and clarithromycin

Li Qi, Wang Yujin, Wang Xueyu, Chu Naihui(), Nie Wenjuan()   

  1. Tuberculosis Department I, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
  • Received:2024-11-04 Online:2025-02-10 Published:2025-02-08
  • Contact: Nie Wenjuan, Email: xiaobingxiaomei@sina.cn;Chu Naihui, Email: chunaihui1994@sina.com
  • Supported by:
    National Natural Science Foundation of China(82100002)

摘要:

目的: 探究新药舒达吡啶对肝酶的作用情况,以及与克拉霉素的相互作用。方法: 取大鼠肝微粒体/人肝微粒体,加入细胞色素P450(cytochrome P450, CYP450)探针底物混合工作溶液。分别加入不同浓度的舒达吡啶、克拉霉素工作溶液,取上清液进行液相色谱-串联质谱(liquid chromatography-mass spectrometry/mass spectrometry, LC-MS/MS)分析。以标准曲线法计算体系中代谢物浓度,计算代谢物的生成量,根据溶剂对照组的变化量,计算剩余活性。结果: 在人肝微粒体试验条件下,舒达吡啶在0.1、0.5、1.5、5、10、25、50、100μmol/L的浓度下,对CYP1A2、CYP2B6、CYP2C8、CYP3A4/5显示微弱抑制强度,对CYP2C9、CYP2C19和CYP2D6显示中等强度或强抑制作用;CYP2C9的半数抑制浓度(inhibitory concentration 50%, IC50)为5.533μmol/L,CYP2C19为<0.1μmol/L,CYP2D6为15.59μmol/L。在大鼠肝微粒体试验条件下,舒达吡啶在0.1、0.5、1.5、5、10、25、50、100μmol/L浓度下,对CYP1A2、CYP2B6、CYP2C9、CYP3A4/5显示微弱抑制强度,对CYP2C8、CYP2C19和CYP2D6显示中等强度抑制作用;CYP2C8的IC50为49.70μmol/L,CYP2C19为10.06μmol/L,CYP2D6为17.55μmol/L。在人肝微粒体试验中,克拉霉素在1、2、5、10、50、100、150和200μmol/L浓度下,对舒达吡啶有抑制作用,IC50为22.74μmol/L;在大鼠肝微粒体试验中,克拉霉素在1、2、5、10、50、100、150和200μmol/L浓度下,对舒达吡啶有轻微抑制作用,IC50为85.61μmol/L。结论: 在人肝微粒体中,舒达吡啶对CYP2C9和CYP2D6有中等强度抑制作用;在大鼠肝微粒体中,舒达吡啶对CYP2C19和CYP2D6有中等强度的抑制作用。在人肝微粒体中,克拉霉素对舒达吡啶的抑制作用较强。

关键词: 分枝杆菌属, 克拉霉素, 舒达吡啶, 药理作用分子作用机制

Abstract:

Objective: To explore the effect of the new drug sudapyridine (WX-081) on liver enzymes and its interaction with clarithromycin. Methods: Take rat liver microsomes/human liver microsomes and add a mixture of cytochrome P450 (CYP450) probe substrates to the working solution. Add sudapyridine and clarithromycin working solutions of different concentrations, and take the supernatant for liquid chromatography mass spectrometry (LC-MS/MS) analysis. Calculate the concentration of metabolites in the system using the standard curve method, calculate the amount of metabolites generated, and calculate the remaining activity based on the changes in the solvent control group. Results: Under the conditions of human liver microsomal assay, sudapyridine showed weak inhibitory effects on CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 at concentrations of 0.1, 0.5, 1.5, 5, 10, 25, 50, and 100 μmol/L, and moderate or strong inhibitory effects on CYP2C9, CYP2C19, and CYP2D6; The inhibitory concentration 50% (IC50) of CYP2C9 was 5.533 μmol/L, CYP2C19 was <0.1 μmol/L, and CYP2D6 was 15.59 μmol/L. Under the conditions of rat liver microsomal assay, sudapyridine showed weak inhibitory effects on CYP1A2, CYP2B6, CYP2C9, and CYP3A4/5 at concentrations of 0.1, 0.5, 1.5, 5, 10, 25, 50, and 100 μmol/L, and moderate inhibitory effects on CYP2C8, CYP2C19, and CYP2D6; The IC50 of CYP2C8 was 49.70 μmol/L, CYP2C19 was 10.06 μmol/L, and CYP2D6 was 17.55 μmol/L. In the human liver microsomal assay, clarithromycin showed inhibitory effects on sudapyridine at concentrations of 1, 2, 5, 10, 50, 100, 150, and 200 μmol/L, with an IC50 of 22.74 μmol/L; In the rat liver microsomal assay, clarithromycin showed a slight inhibitory effect on sudapyridine at concentrations of 1, 2, 5, 10, 50, 100, 150, and 200 μmol/L, with an IC50 of 85.61 μmol/L. Conclusion: Sudapyridine has a moderate inhibitory effect on CYP2C9 and CYP2D6 in human liver microsomes; sudapyridine has a moderate inhibitory effect on CYP2C19 and CYP2D6 in rat liver microsomes. In human liver microsomes, clarithromycin has a strong inhibitory effect on sudapyridine.

Key words: Mycobacterium, Clarithromycin, WX-081, Molecular mechanisms of pharmacological action

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