INTESTINAL-ABSORPTION SCREENING OF MIXTURES FROM COMBINATORIAL LIBRARIES IN THE CACO-2 MODEL

Purpose. Understanding how chemical structures influence transport acr oss the intestinal mucosa will greatly enhance the discovery of orally available drugs. In an attempt to accelerate defining such relationsh ips between structure and transport, six arbitrary mixtures of N-subst ituted glycine (NSG) peptoids containing 24 physicochemically diverse compounds were evaluated in the Caco-2 model of intestinal absorption. Methods. Samples were analyzed by HPLC and the areas of the peaks rep resenting the components of each mixture were summed to measure ''aggr egate'' apparent permeability coefficients (P-app), a score of the inf luence of the common structural element within each mixture towards ab sorption. Mass spectrometry was used to identify the chemical structur e of Caco-2 permeable compounds. Results. Three linear trimeric mixtur es were examined and, for each mixture, none of the components was det ected in receiver chambers. It was concluded that the components of th ese mixtures each had a P-app value less than 0.8 x 10(-6) cm/sec, a p ermeability less than mannitol. Three dimeric mixtures were examined a nd they exhibited aggregate P-app values of 9.2 x 10(-6), 14 x 10(-6) and 6.9 x 10(-6) cm/sec. These transport rates reflected the transport of most of the components of each mixture. Furthermore, the component s of the dimeric mixtures which were transported at a rate greater tha n mannitol were apparently transported by passive mechanisms. Conclusi ons. This study demonstrated that mixtures can be used to study struct ure-transport relationships in the Caco-2 model. The information obtai ned from this type of study will be integrated into the design of futu re chemical libraries. Other potential uses of chemical mixtures with the Caco-2 model are also discussed.