透性文献数据的元分析显示了流行方法的可能性和局限性
Kateřina Storchmannová1, Martin Balouch2,3, Jakub Juračka1,4
1Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
Molecular pharmaceutics
|February 20, 2025
概括
药物透性测量可重复性在各种方法中很差. 基于细胞的测试和计算模型显示出最好的协议,但每个都有局限性. 在解释透性数据时,建议谨慎.
科学领域:
- 药物的发现和开发.
- 药物动力学和分子特性
- 膜运输和生物物理学
背景情况:
- 分子透性对药物药理动力学至关重要,它会影响通过肠道和血脑屏障等生物膜的吸收.
- 有许多实验 (基于细胞的测定,PAMPA,BLM,脂质体) 和计算方法用于透度的确定.
- 现有的透性数据库 (MolMeDB,ChEMBL) 需要对药物发现应用进行可用性评估.
研究的目的:
- 评估各种测量分子透性的实验和计算方法的可用性和一致性.
- 确定从不同来源解释和结合透性数据的局限性和最佳实践.
- 通过各种方法评估透性测量的可重复性和一致性.
主要方法:
- 公开的透性数据库的元分析 (MolMeDB,ChEMBL).
- 评估了四种实验方法:CACO-2,MDCK,PAMPA (并行人工膜透性测定) 和BLM (黑色脂质膜).
- 与两个in silico计算透性预测方法的比较.
主要成果:
- 透度测量的可重复性是低于最佳的,即使是在相同的方法内.
- 基于细胞的测定和计算方法显示出最好的一致性,而PAMPA显示出差异 (内在与明显的透性).
- 不水层 (UWL) 的透性会影响数据的一致性,特别是在基于细胞的/明显的PAMPA和UWL独立的方法 (计算,BLM,内在的PAMPA) 之间.
结论:
- 不同的透性评估方法具有明显的限制,影响数据解释.
- 基于细胞的方法仅限于狭窄的透度范围,而计算方法提供了更广泛的预测,精度降低.
- 黑色脂质膜 (BLM) 与脂质体具有广泛的透性,但使用起来更复杂;在解释和结合透性数据时建议谨慎使用.
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