对发育性神经毒性的生理学基础的药物动力学建模平台的比较 in vitro 到 in vivo 抽外推理
Anna Kreutz1, Xiaoqing Chang1, Michael Lawless2
1Inotiv, RTP, NC 27560, United States.
概括
本研究提出了一种体外到体外抽取 (IVIVE) 方法,以将发育性神经毒性 (DNT) 测定结果转化为与人类相关的剂量. 这种方法有助于进行风险评估,通过将体外发现与人类潜在暴露进行比较.
科学领域:
- 毒理学 毒理学 毒理学
- 药理动力学 药理动力学
- 风险评估 风险评估
背景情况:
- 在体外测定发育性神经毒性 (DNT) 对传统的体内研究具有优势.
- 一个关键的挑战是将体外度转化为体外剂量,以评估风险.
- 现有的方法缺乏有效的方式来比较体外发现与人类暴露水平.
研究的目的:
- 开发和评估DNT的体外到体外抽取 (IVIVE) 方法.
- 从体外DNT测定数据中得出与人类相关的同等剂量 (AED).
- 评估DNT-IVIVE方法在不同基于生理学的药理动力学建模平台上的可转移性.
主要方法:
- 利用了美国环保署 (EPA) 进行的17项体外DNT测定中的7项数据.
- 应用了三种基于生理学的药理动力学 (PBPK) 建模平台,用于IVIVE.
- 在大脑发育过程中基于DNT目标器官的化学分离计算AED.
主要成果:
- 在DNT-IVIVE方法中,78%的测试化学物质的AED在体内效应水平的三倍之内.
- 来自IVIVE方法的抗体被与风险评估指标预测的人类暴露相比较.
- IVIVE方法在评估的PBPK建模平台中显示出相对的可转移性.
结论:
- 开发的DNT-IVIVE方法提供了一种可行的方法,用于将体外DNT数据转化为与人类相关的剂量.
- 这种方法促进了风险评估,因为它可以将体外生物活性与人类潜在暴露进行比较.
- 虽然可以转移,但DNT-IVIVE方法对不同的建模平台和使用环境有局限性和具体考虑.
相关概念视频
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