Centre for Drug Candidate Optimisation - Disciplines

Cell Based Assays

In vitro assessment of drug permeability

Permeability across the gastrointestinal mucosa is one of a number of critical factors that determine whether or not a compound will be absorbed following oral administration. Poor permeability (which can arise due to a number of structural features), as well as the potential for membrane-based efflux mechanisms, generally leads to poor absorption and low oral bioavailability.

There are several approaches used by the Centre to assess the permeability of new drug candidates, with the most widely employed in vitro model being Caco-2 cell monolayers (see diagram). Using this model system, the permeation of compounds across the monolayer is used to determine an apparent permeability coefficient, which allows the ranking of compounds as either highly permeable, moderately permeable or poorly permeable relative to well characterised drug standards. The Centre has thoroughly validated this model to ensure that the permeability coefficients for drug standards are consistent with literature values and that variability is minimised. The model can also be used to determine the potential for active uptake by transporter proteins or efflux by transporters such as p-glycoprotein.

Another approach utilised for the assessment of passive membrane permeability is the parallel artificial membrane assay (PAMPA), in which drug permeation across a model lipid bilayer is determined. This system is rapid and useful for the identification of compounds whose permeability is likely to be limited by their structural properties.

By using these two in vitro approaches for assessing drug permeability, together with knowledge of a compound's physicochemical properties (in vitro metabolic lability and in vivo absorption), the Centre is well placed to determine which factors are most likely to limit oral absorption and bioavailability. This information informs further synthetic strategies and the need for structural modification within a compound series.