通过一种新方法方法量化人类个体间动力学差异对低剂量里德利林N-氧化物相对强度值的影响
F Widjaja-van den Ende1, M A J S van Boekel2, C Davis3
1Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands.
Regulatory toxicology and pharmacology : RTP
|December 22, 2024
概括
罗化类N-氧化物 (PA-N-氧化物) 在体内转化为有毒的罗化类化物 (PA). 个体间的差异显著影响了PA-N-氧化物与PA的相对强度,特别是在低剂量时.
科学领域:
- 药理动力学和毒理学
- 植物性毒素的新陈代谢
- 对食化合物的风险评估
背景情况:
- 罗利胺甲基N-氧化物 (PA-N-氧化物) 在草药产品中很常见,可以转化为有毒的罗利胺甲基 (PA).
- 了解PA-N-氧化物转化为PA的个体间变异性对于准确的毒性评估至关重要.
- 作为研究这些差异的模型化合物,Riddelliine N-oxide (RIDO) 和riddelliine (RID) 被用作模型化合物.
研究的目的:
- 量化个体间动力学差异对PA-N-氧化物与其原始PA相比相对强度的影响 (REPPANO到PA).
- 开发一种方法来确定低剂量的REPPANO到PA值,这些值在体内很难评估.
- 为了建模REPRIDO到RID值的概率分布,考虑到人类的变化.
主要方法:
- 在实验室内从30个便和25个肝脏S9供体样本的化过程中收集了动力学数据.
- 用贝叶斯的多级回归来捕捉动力参数中显著的个体间变异性.
- 基于生理学的动力学 (PBK) 建模与蒙特卡洛 (MC) 模拟相结合,用于计算REPRIDO到RID分布.
主要成果:
- 在PA-N-氧化物转化为PA的动力学数据中观察到高度的个体间变异.
- 研究人员发现,在低剂量水平下,个体间的差异会影响REPRIDO到RID值.
- 计算的REPRIDO到RID分布范围从0.71到0.97 (95百分位数),平均值为0.87.
结论:
- 该研究使用PBK和MC模拟成功模拟了PA-N-氧化物转化为PA的个体间差异.
- 开发的方法允许在低剂量下确定个体间的REPPANO到PA值.
- 该方法为在饮食暴露场景中对PA-N-氧化物进行风险评估提供了有价值的工具.
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