Selection of development candidates based on in vitro permeability measurements

Based on the desire to develop orally active drug candidates, approaches have been evaluated to identify molecules with characteristics which not only allow them to be potent at their specific receptor but also to have the appropriate membrane properties to allow absorption across the cells lining the gastrointestinal tract. The Ussing chamber approach has been instrumental in advancing our understanding of the mechanisms involved in drug transport and is also being employed to screen large numbers of compounds for selection of clinical candidates. From these types of studies, it has been demonstrated that synthesis of an amino acid prodrug of the nucleoside antiviral, acyclovir, provides an approach for enhancing uptake across the apical cell membrane with subsequent intracellular hydrolysis and release of the parent molecule across the basolateral membrane. It is these types of approaches which should provide a more rapid and rational method for identification of clinical candidates in the future.