Permeability Coefficients of Lipophilic Compounds Estimated by Computer Simulations

The ability of a
drug to cross the intestine–blood barrier
is a key quantity for drug design and employment and is normally quantified
by the permeability coefficient P, often evaluated
in the so-called Caco-2 assay. This assay is based on measuring the
initial growth rate of the concentration of the drug beyond the cellular
barrier but not its steady-state flux through the membrane. This might
lead to confusion since, in the case of lipophilic drugs, the initial
slope is strongly affected by the retention of the drug in the membrane.
This effect is well known but seldom considered in the assay. Here,
we exploit all-atoms molecular dynamics and bias exchange metadynamics
to calculate the concentration of two lipophilic drugs across a model
membrane as a function of time. This allows estimating both the steady-state
flux and the initial slope of the concentration growth and comparing
Caco-2 and steady-state estimates of P. We show that
our computational procedure is able to reproduce the experimental
values, although these may differ from the permeability coefficients
by orders of magnitude. Our findings are generalized by a simplified
one-dimensional model of the permeation process that may act as a
roadmap to assess which measure of membrane permeability would be
more appropriate and, consequently, whether retention corrections
should be included in estimates based on Caco-2 assays.