常见体外系统的实用性用于预测循环中的代谢物
Elyse C Freiberger1, Michael P Thompson1, Xiaomei Zhang1
1AbbVie Inc., North Chicago, Illinois.
Drug metabolism and disposition: the biological fate of chemicals
|October 21, 2024
概括
实验室药物代谢研究预测了大约一半的人类代谢物,但没有量化水平. 悬浮和共同培养的肝细胞显示出稍微更好的代谢物预测准确性.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药物新陈代谢 药物新陈代谢
- 毒理学 毒理学 毒理学
背景情况:
- 在体外系统对于早期药物开发至关重要,可以预测人类代谢物,并指导毒性研究的临床前物种选择.
- 然而,体外模型对体外结果的预测准确性可能是可变的,因此需要更清楚地了解它们的可靠性.
- 评估体外和体内代谢物概况之间的相关性对于降低风险的药物开发决策至关重要.
研究的目的:
- 评估体外系统预测体内观察到的循环代谢物的能力.
- 为了确定体外系统的预测性是定量性的还是仅仅表明代谢物存在的.
- 为了比较常见的体外肝脏模型在产生人类药物代谢的预测代谢物的性能.
主要方法:
- 对Abbott/AbbVie的历史代谢物分析数据进行了回顾性分析,比较了体外和体外 (吸收,分布,代谢,分泌和临床) 研究结果.
- 在五个体外系统中化了10种已公布的代谢数据的商用化合物:微粒,肝脏S9,悬浮肝细胞,HμREL共培肝细胞和肝细胞球体.
- 新的体外代谢物分析数据被生成并与已发布的体内数据进行比较,以评估每个系统在预测已知的主要人类循环代谢物的准确性.
主要成果:
- 在体外系统预测了在临床前物种和人类体内体内发现的循环代谢物的约50%.
- 在体外测量代谢物度和体内发现的代谢物度之间没有观察到定量相关性.
- 悬浮肝细胞和共同培养的肝细胞在预测已知的主要人类循环代谢物方面略高于其他经过体外测试的系统.
结论:
- 当前的体外系统对于早期药物开发非常有价值,当体内研究不可行时,以及支持临床前毒理学物种选择的监管文件.
- 虽然体外系统预测了大约一半的循环代谢物的存在,但它们没有提供定量水平预测.
- 没有单一的体外系统能够绝对优于其他系统,尽管悬浮和共培肝细胞显示出略有更好的预测性能;这些系统不应该被认为完全代表体内药物代谢.
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