Grant: Collaborative Health Research Projects

Poor intestinal absorption is a major bottleneck in drug discovery as promising new chemical entities often lacksuitable amphiphilic balance required for absorption. No one knows how many acceptable candidates havebeen discarded from the discovery pipeline although their bioavailability could have been significantlyimproved. Inappropriate in vitro prediction of drug bioavailability is suspected as one of the reasons explainingthe rejection of many promising drug candidates from development after time and millions invested inresearch. The challenge is, thus, to provide just-in time information about drug-like properties to orient themedicinal chemistry lead optimization effort. Parallel artificial membrane permeability assay (PAMPA) is awell-established and simple in vitro model that however lacks biological relevance and reliability. It assessespassive intestinal permeation - the principal route for drug absorption. The objectives of our project are (1) toenhance the PAMPA technology by developing new membranes more representative of the gut cell lipid wallsand (2) to make it amenable to HTS and non-specialized lab personnel. We will thus develop phospholipidfloating membranes on polymer cushion amenable to Franz cells and multi-well plate setup. This project, incollaboration with an industrial partner, combines a robust technology well-known in the pharmaceutical fieldto a recent advance in bilayer fluidity devices (polymer-supported membranes) to develop a new assay of drugpermeability. It is enabled by the combination of expertises in lipid physicochemistry, polymer science andbiopharmacy. The use of this new PAMPA in R&D labs should accelerate the discovery of new drug therapies,reduce the number of discarded promising drugs, and provide more drugs with improved bioavailability andreduced risks of side effects due to too high dosage. The impact on the health of the Canadians should be major- less people should suffer of side effects, and more drug therapies should be available for the treatment ofdiseases that are affecting the population. Economically, our project will have a positively impact the Canadianpharmaceutical industry and health system.