IDEAYA Biosciences, South San Francisco, California 94080, United States.
Global Blood Therapeutics, South San Francisco, California 94080, United States.
J Med Chem. 2022 Jul 14;65(13):8713-8734. doi: 10.1021/acs.jmedchem.2c00502. Epub 2022 Jul 5.
The "free drug hypothesis" assumes that, in the absence of transporters, the steady state free plasma concentrations equal to that at the site of action that elicit pharmacologic effects. While it is important to utilize the free drug hypothesis, exceptions exist that the free plasma exposures, either at , , and , or at other time points, cannot represent the corresponding free tissue concentrations. This "drug concentration asymmetry" in both total and free form can influence drug disposition and pharmacological effects. In this review, we first discuss options to assess total and free drug concentrations in tissues. Then various drug design strategies to achieve concentration asymmetry are presented. Last, the utilities of tissue concentrations in understanding exposure-effect relationships and translational projections to humans are discussed for several therapeutic areas and modalities. A thorough understanding in plasma and tissue exposures correlation with pharmacologic effects can provide insightful guidance to aid drug discovery.
“游离药物假说”假设，在不存在转运体的情况下，药物的稳态游离血浆浓度等于在发挥药效的作用部位的浓度。虽然利用游离药物假说很重要，但也存在例外情况，即游离血浆暴露水平，无论是在 、 、 或其他时间点，都不能代表相应的游离组织浓度。这种在总浓度和游离浓度形式上的“药物浓度不对称性”会影响药物的处置和药理作用。在这篇综述中，我们首先讨论了评估组织中总药物和游离药物浓度的方法。然后介绍了几种实现浓度不对称的药物设计策略。最后，讨论了在几个治疗领域和治疗方式中，理解组织浓度与暴露-效应关系和向人体转化的应用。深入了解与药理作用相关的血浆和组织暴露之间的关系，可以为药物发现提供有见地的指导。
