Cordeiro Margarida M, Salvador Armindo, Moreno Maria João
Coimbra Chemistry Centre-Institute of Molecular Sciences (CQC-IMS), University of Coimbra, 3004-535 Coimbra, Portugal.
Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Membranes (Basel). 2022 Feb 23;12(3):254. doi: 10.3390/membranes12030254.
Predicting the rate at which substances permeate membrane barriers in vivo is crucial for drug development. Permeability coefficients obtained from in vitro studies are valuable for this goal. These are normally determined by following the dynamics of solute equilibration between two membrane-separated compartments. However, the correct calculation of permeability coefficients from such data is not always straightforward. To address these problems, here we develop a kinetic model for solute permeation through lipid membrane barriers that includes the two membrane leaflets as compartments in a four-compartment model. Accounting for solute association with the membrane allows assessing various methods in a wide variety of conditions. The results showed that the often-used expression = × /3 is inapplicable to very large or very small vesicles, to moderately or highly lipophilic solutes, or when the development of a significant pH gradient opposes the solute's flux. We establish useful relationships that overcome these limitations and allow predicting permeability in compartmentalised in vitro or in vivo systems with specific properties. Finally, from the parameters for the interaction of the solute with the membrane barrier, we defined an intrinsic permeability coefficient that facilitates quantitative comparisons between solutes.
预测体内物质透过膜屏障的速率对于药物开发至关重要。从体外研究获得的渗透系数对于实现这一目标很有价值。这些系数通常通过追踪两个由膜分隔的隔室之间溶质平衡的动态过程来确定。然而，从这些数据正确计算渗透系数并非总是易事。为了解决这些问题，我们在此开发了一种溶质透过脂质膜屏障的动力学模型，该模型在一个四隔室模型中将两个膜小叶作为隔室。考虑溶质与膜的结合能够在各种条件下评估多种方法。结果表明，常用表达式 = × /3 不适用于非常大或非常小的囊泡、中等或高度亲脂性溶质，或者当显著的pH梯度发展阻碍溶质通量时。我们建立了有用的关系，克服了这些限制，并能够预测具有特定特性的体外或体内分隔系统中的渗透性。最后，根据溶质与膜屏障相互作用的参数，我们定义了一个固有渗透系数，便于溶质之间的定量比较。
