CYP3A4和CYP2C19遗传多态性和myricetin对托法西提尼布代谢的相互作用
Zhize Ye1, Hailun Xia2, Jinyu Hu2
1The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
概括
遗传变异和myricetin显著影响到facitinib的代谢. 这项研究为个性化类风湿性关节炎治疗策略提供了关键数据.
科学领域:
- 药理学 药理学是指药理学的学科.
- 遗传学 是一个遗传学.
- 药物新陈代谢 药物新陈代谢
背景情况:
- 类风湿性关节炎 (RA) 是一种慢性自身免疫性疾病,可以用诸如托法西提尼布 (tofacitinib) 等药物治疗.
- 了解托法西提尼布代谢对于优化RA治疗至关重要.
- 药物代谢酶的遗传变异可以改变药物的疗效和安全性.
研究的目的:
- 研究复合CYP2C19和CYP3A4变异对托法西提尼布代谢的影响.
- 为了分析托法西替尼和myricetin之间的体外相互作用.
- 为准确地在RA患者中应用托法西提尼布提供数据.
主要方法:
- 利用复合人体CYP2C19和CYP3A4系统来评估托法西替尼的代谢.
- 使用超高性能液态染色体协同质谱法 (UPLC-MS/MS) 量化了主要代谢物M9.
- 在小鼠和人类肝脏显微体中使用myricetin进行了体外抑制测定,以及特定的CYP变体.
主要成果:
- 与CYP2C19.1相比,CYP2C19的11种变体显著改变了M9水平,其中10种显示下降.
- 与CYP3A4.1.1相比,11种CYP3A4变体显著改变了M9水平.
- 米瑞在RLM和HLM中表现出非竞争性抑制,在CYP3A4.18中表现出竞争性抑制,在CYP3A4.1和CYP3A4.28中表现出混合性抑制.
结论:
- 在CYP2C19和CYP3A4中的基因多态性显著影响托法西替尼的代谢.
- 瑞通过各种抑制机制与托法西提尼布代谢相互作用.
- 这些发现支持基于遗传特征和潜在药物相互作用的个性化托法西提尼布剂量策略.
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