caa a22 4500 477127932 CHVBK 20180405111655.0 cr unu---uuuuu 170330e19970501xx s 000 0 eng 10.1023/A:1012140709158 doi (NATIONALLICENCE)springer-10.1023/A:1012140709158 Intestinal Absorption Screening of Mixtures from Combinatorial Libraries in the Caco-2 Model [Elektronische Daten] [Eric Taylor, Jacqueline Gibbons, Rene Braeckman] Purpose. Understanding how chemical structures influence transport across the intestinal mucosa will greatly enhance the discovery of orally available drugs. In an attempt to accelerate defining such relationships between structure and transport, six arbitrary mixtures of N-substituted 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 representing the components of each mixture were summed to measure 'aggregate' apparent permeability coefficients (P app) a score of the influence of the common structural element within each mixture towards absorption. Mass spectrometry was used to identify the chemical structure of Caco-2 permeable compounds. Results. Three linear trimeric mixtures were examined and, for each mixture, none of the components was detected in receiver chambers. It was concluded that the components of these mixtures each had a P app value less than 0.8 × 10−6 cm/sec, a permeability less than mannitol. Three dimeric mixtures were examined and they exhibited aggregate P app values of 9.2 × 10−6 , 14 × 10−6 and 6.9 × 10−6 cm/sec. These transport rates reflected the transport of most of the components of each mixture. Furthermore, the components of the dimeric mixtures which were transported at a rate greater than mannitol were apparently transported by passive mechanisms. Conclusions. This study demonstrated that mixtures can be used to study structure-transport relationships in the Caco-2 model. The information obtained from this type of study will be integrated into the design of future chemical libraries. Other potential uses of chemical mixtures with the Caco-2 model are also discussed. Plenum Publishing Corporation, 1997 Caco-2 nationallicence intestinal absorption nationallicence structure-transport relationships nationallicence structure-activity relationships (SAR) nationallicence mixtures nationallicence combinatorial chemistry nationallicence Taylor Eric Pharmacokinetics Department, Biopharmaceutical Evaluation, Chiron Corporation, 4560 Horton Street, Emeryville, California aut Gibbons Jacqueline Pharmacokinetics Department, Biopharmaceutical Evaluation, Chiron Corporation, 4560 Horton Street, Emeryville, California aut Braeckman Rene Pharmacokinetics Department, Biopharmaceutical Evaluation, Chiron Corporation, 4560 Horton Street, Emeryville, California aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/5(1997-05-01), 572-577 0724-8741 14:5<572 1997 14 11095 https://doi.org/10.1023/A:1012140709158 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012140709158 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Taylor Eric Pharmacokinetics Department, Biopharmaceutical Evaluation, Chiron Corporation, 4560 Horton Street, Emeryville, California aut NATIONALLICENCE 700 1- Gibbons Jacqueline Pharmacokinetics Department, Biopharmaceutical Evaluation, Chiron Corporation, 4560 Horton Street, Emeryville, California aut NATIONALLICENCE 700 1- Braeckman Rene Pharmacokinetics Department, Biopharmaceutical Evaluation, Chiron Corporation, 4560 Horton Street, Emeryville, California aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/5(1997-05-01), 572-577 0724-8741 14:5<572 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer