TY - JOUR T1 - Stereoselective Interaction of Pantoprazole with ABCG2. II. In Vitro Flux Analysis JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1024 LP - 1031 DO - 10.1124/dmd.111.041616 VL - 40 IS - 5 AU - Lipeng Wang AU - Markos Leggas AU - Philip E. Empey AU - Patrick J. McNamara Y1 - 2012/05/01 UR - http://dmd.aspetjournals.org/content/40/5/1024.abstract N2 - (−)Pantoprazole [(−)PAN] accumulated in rat milk stereoselectively, and this accumulation was attributed to rat Abcg2 (rAbcg2). In contrast, flux experiments at 25 μM showed that (+)pantoprazole [(+)PAN] was preferentially transported by rAbcg2. The purpose of the current study was to comprehensively evaluate the transport of PAN isomers in empty-Madin-Darby canine kidney II (MDCKII) and MDCKII cells expressing the human/rat (ABCG2/rAbcg2) isoforms at concentrations ranging from 3 to 200 μM. The apical-to-basolateral and basolateral-to-apical directional flux and the asymmetry efflux ratios were virtually identical for both isomers in empty (mock transfected)-MDCKII monolayers but were concentration dependent for both isomers in ABCG2 (human/rat)-MDCKII. Kinetic analysis using predicted cellular concentrations showed that (−)PAN had an 8-fold lower KM compared with (+)PAN for both rAbcg2 (0.25 versus 1.85 μM) and ABCG2 (0.6 versus 5.32 μM). (+)PAN had a 3-fold higher TMax compared with the (−)PAN for both rAbcg2 (7.86 versus 2.49 nmol/h · cm2) and ABCG2 (10.2 versus 3.29 nmol/h · cm2). Effective ABCG2 surface-area permeability of (−)PAN was 9920 and 5480 (μl/h)/cm2 for rAbcg2 and ABCG2, respectively, compared with the (+)PAN isomer (4250 and 1920 μl/h · cm2, respectively). These results indicate a stereoselective interaction of PAN with similar kinetic parameters for both human and rat ABCG2. (−)PAN is a better substrate than (+)PAN for ABCG2/rAbcg2 and provide a rationale for the preferential accumulation of (−)PAN into rat milk. ER -