Atomistic Modeling of Drug Permeability

Membrane free energy profiles and diffusion coefficients for one hydrophilic (atenolol) and one lipophilic drug molecule (progesterone), as reported by Orsi and Essex (Orsi and Essex, Soft Matter, 2010, 6, 3797–3808) are used as input for a cell model in order to calculate the drug permeability across a Caco-2 cell monolayer. One key observation from these studies is that strongly hydrophilic molecules diffuse along the membrane leaflet rather than through the cell cytoplasm. For such molecules, a free energy barrier in the inner “tail region” of the membrane prevents diffusion in a direction normal to the membrane. We argue that the molecular free energy function is the essential quantity that determines the passive intrinsic permeability of drug molecules. These insights may also play a role on understanding how efficiently CYP3A4 substrates are metabolized (intracellularly) in the intestine after oral administration.