Novartis Institutes for Biomedical Research, Metabolism and Pharmacokinetics, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
Expert Opin Drug Metab Toxicol. 2010 Feb;6(2):171-87. doi: 10.1517/17425250903436486.
Adequate permeability is essential for good oral absorption and proper interpretation of pharmacokinetic and pharmacological data. Permeability-limiting absorption and distribution, however, are complex phenomena involving multiple mechanisms and organs ranging from gastro-intestine, liver, kidney to BBB, while the options for pharmaceutical improvement of permeability are quite limited.
In this article, the comprehensive in silico, in vitro and in vivo/ex vivo/in situ tools to assess permeability are reviewed, alongside their advantages and limitations. Several key points relating to the in vivo predictive impact of in vitro permeability tools and the caveats when dealing with challenging discovery compounds were also addressed, using drug discovery cases and statistics in Novartis.
The integrated strategy to properly utilize existing permeability tools for mitigating the permeability-related absorption or safety risks at the different stages of drug discovery and development processes is presented.
It is critical to utilize the comprehensive in silico, in vitro and in vivo/ex vivo tools to dial out permeability issues in early drug discovery, ensuring the right questions to be addressed using the right tools at the right time.
足够的通透性对于良好的口服吸收和正确解释药代动力学和药效学数据至关重要。然而，通透性限制的吸收和分布是复杂的现象，涉及从胃肠道、肝脏、肾脏到 BBB 的多种机制和器官，而改善通透性的药物选择相当有限。
本文综述了评估通透性的综合计算机模拟、体外和体内/体外/原位工具，以及它们的优缺点。还使用诺华的药物发现案例和统计数据，讨论了体外通透性工具对体内预测的影响以及在处理具有挑战性的发现化合物时的注意事项。
提出了一种综合策略，以正确利用现有的通透性工具，在药物发现和开发过程的不同阶段减轻与通透性相关的吸收或安全性风险。
在早期药物发现中利用综合的计算机模拟、体外和体内/体外工具排除通透性问题至关重要，确保在正确的时间使用正确的工具解决正确的问题。
