Cloe Screen MDR1-MDCK: A Predictive Model of Drug Permeability
Poster Jan 04, 2007
David Turner, Boris Pufong, Susan Hinchliffe, Gayle Corkill, Deborah Slamon, Peter Dykstra, Helen Gill, Clive Dilworth and Darwin Cheney
Madin Darby Canine Kidney cells transfected with the human MDR1 gene (MDR1-MDCK), express the membrane transporter P-glycoprotein (P-gp). We have developed an MDR1-MDCK permeability screen for assessing the membrane permeability properties of early drug discovery compounds.
This study measured the bi-directional transport of compounds with a range of permeabilities across MDR1-MDCK monolayers. Drug concentrations were analysed by LC-MS/MS, from which apparent permeability (Papp) values in apical-basolateral (A-B) and basolateral-apical (B-A) directions and asymmetry index (B-A Papp /A-B Papp) were calculated. Experiments were also carried out in the presence or absence of the P-gp inhibitor cyclosporin A.
Results were compared with those from Caco-2 permeability studies as well as human intestinal absorption values and brain uptake classification obtained from literature. These results indicate that Cloe Screen MDR1-MDCK permeability assay is a useful predictive tool for assessing human intestinal absorption and uptake across the blood brain barrier in early drug discovery.
During early drug discovery, the study of metabolism plays an essential role in determining which drug candidates move forward into development and later stages. As an alternative to traditional Data Dependent Acquisition (DDA), the use of MSE/All Ions Fragmentation (AIF) has become common in metabolite identification workflows for the analysis of metabolic hot spots. Here we present a solution for analysis of MSE/AlF in metID studies.READ MORE