Calculation of Permeability Coefficients from Solute Equilibration Dynamics: An Assessment of Various Methods

Margarida M Cordeiro,Armindo Salvador,Maria João Moreno

doi:10.3390/membranes12030254

Abstract

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 Papp = β × r/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.

Highlights

To reach their target sites from the site of administration, drugs must cross a series of biological membranes
In this work we develop a kinetic model that allows the description of the dynamics of solute equilibration between two aqueous compartments separated by a lipid membrane
This is an important parameter that is independent of system topology, and may be used to calculate the rate of equilibration in any system that is compartmentalised by lipid membranes

Summary

Introduction

To reach their target sites from the site of administration, drugs must cross a series of biological membranes. Insufficient permeability through any of these membranes is a major cause of attrition in drug development. For this reason, much effort has been devoted to characterise the rate of permeation of large sets of drug-like molecules, seeking to achieve predictive power. Multiple experimental methodologies have been developed for this purpose, using either cell monolayer membranes, [1,2,3,4] or simpler lipid membranes [5,6,7,8,9]. Simpler model systems such as lipid membranes are required

Methods

Results

Conclusion