Permeability is important in governing the ability of drug substances to transport across gastrointestinal membrane
and also crucial for proper drug distribution to pharmacological target organs and cells, and is therefore frequently
utilized in drug discovery and development. In this report, we have performed a systematic analysis, using principal component
analysis on the historically measured permeability data from in-house Caco-2 and parallel artificial membrane
permeability assays on discovery new chemical entities from multiple projects. This work allows for establishment of a
permeability diagnosis model by purposefully identifying most influencing physicochemical properties of the permeability
issues, including polarity-lipophilicity line contributed primarily by polar surface area and LogP, number of rotation bond,
fractional ionization at neutral pH and efflux ratio. A number of cases were also shown to demonstrate the applicability of
the current model. The analysis of the model over internal drug discovery compounds exhibited promising diagnostic and
predictive power of the model. The advantages and limitation of the model as well as the integral strategy to apply it in
drug discovery to guide projects for permeability-related optimization were also presented.
Keywords: Permeability diagnosis, ADME, oral absorption, gastrointestinal permeability, transporter, Caco-2 and PAMPA.
open access plus
Rights & PermissionsPrintExport