RESEARCH & DEVELOPMENT
How to Study Drug Transport at Biological Interfaces To design drugs with better absorption and distribution, scientists need to have a comprehensive understanding of the transport mechanism of drugs at biological interfaces. Thus, developing techniques capable of monitoring transport in real-time is crucial for pharmaceutical industries. Currently, fluorescence, SPR, and SHS are the most state-of-the-art approaches. Mohammad Sharifian, Department of Cell Biology, University of Virginia
D
rugs as small- or medium-sized molecules (1-2 nanometer in diameter) typically possess both lipophilic and hydrophilic properties. For a drug molecule to reach its intracellular target, it usually needs to cross several barriers including mucus gel layer, intestinal epithelial cells, capillary endothelium, and finally membrane of target cells. In all those interfaces, lipoidal diffusion and protein-mediated passive transport across lipid bilayers play an important role in its molecular entry. Thus, understanding the mechanism of drug transport at biological membranes provides us with a theoretical foundation for designing powerful drugs with better Absorption, Distribution, Metabolism, Excretion, and Toxicology (ADMET) properties. Physicochemical properties of drug molecules, including molecular weight, surface charge, lipophilicity, acid/base properties, number of hydrogen bonds and rings determine their behavior in a solution and at membrane barriers. While the ‘Overton’s rule’ simply states that membrane permeability of a
52
P H A RM A F O C U S A S I A
ISSUE 43 - 2021
permeant, Pm (m s-1) is proportional to the product of its diffusivity, Dp (m2 s-1) and oil/water partition coefficient, Ko/w (unitless), in a quantitative structure-permeability relationship (QSPR) model, drug’s molecular weight, number of aromatic or non-aromatic rings, and hydrogen bond donors and acceptors are utilised to predict permeability of the molecule by which poor permeability is more likely for Ko/w> 100,000, molecular weight > 500 Da, hydrogen bond donors > 5, and hydrogen bond acceptor > 10 1. The anisotropic and inhomogeneous nature of biological membranes has encouraged scientists to develop ‘inhomogeneous solubility-diffusion model’ which
considers depth-dependent partitioning, resistance, and diffusion parameters. As depicted in Figure 1, drug permeation is determined by two main equilibria of drug partitioning between the aqueous compartments and the lipid leaflets, and drug translocation between the two lipid leaflets by which for lipophilic compounds, the membrane may act as both a barrier and a sink. The following equation can be used to estimate the permeability of drug molecules at a lipid bilayer of biological membranes2, where, is the membrane viscosity (kg m-1 s-1), dm is the effective thickness of the membrane, Vp is the volume of the drug molecule (m3), is the size selectivity factor of the permeant, Kc ⁄w is the partition coefficient of drug between water and chloroform, and kB and T are respectively Boltzmann constant (1.38×10-23 m2 kg s-2 K-1), and temperature (K). Model Membrane Systems in Drug Permeation Measurements
A monolayer of cultured colorectal adenocarcinoma-derived cells (Caco-2 cell permeability assay) is widely used to mimic a single layer of intestinal
Note that the universality of a theory or model is limited as the success or failure of each model will be highly dependent on the training set of molecules.Note that the universality of a theory or model is limited as the success or failure of each model will be highly dependent on the training set of molecules.
