使用定量系统毒理学评估单独和组合使用大麻素和氨酸的肝脏影响
Vinal V Lakhani1, Grant Generaux1, Brett A Howell1
1DILIsym Services Inc., A Simulations-Plus Company, Durham, North Carolina, USA.
Clinical pharmacology and therapeutics
|July 17, 2023
概括
大麻素 (CBD) 可以导致肝损伤,特别是当与酸 (VPA) 结合时. 然而,DILIsym模拟表明这种药物相互作用不太可能是由于直接的肝毒性机制.
科学领域:
- 药理学 药理学是指药理学的学科.
- 毒理学 毒理学 毒理学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 大麻 (CBD) 用于治疗德拉维特综合征,伦诺克斯-加斯托综合征和结核性硬化综合症的发作.
- 在临床试验中观察到肝酶 (ALT) 升高,特别是在与酸 (VPA) 联合使用时.
研究的目的:
- 研究在接受CBD和VPA治疗的患者中ALT升高背后的机制.
- 使用DILIsym,一个定量系统毒理平台来建模相互作用.
主要方法:
- 在体外测试评估了CBD,其代谢物和VPA的肝毒性,通过胆酸载体抑制,线粒体功能障碍和ROS产生.
- 基于生理学的药物动力学模型预测了肝脏暴露.
- 在各种治疗场景下,DILIsym模拟了ALT升高.
主要成果:
- DILIsym预测了CBD的剂量依赖ALT升高,主要是由ROS产生的.
- 单独使用VPA就会导致短暂的ALT升高.
- 与临床观察相反,模拟并没有预测VPA之前CBD时ALT升高的发病率增加.
结论:
- 在VPA患者中,与CBD相关的ALT升高显著增加不太可能由研究的三个主要直接肝毒性机制调解.
- 需要进一步的研究来阐明相互作用机制.
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