title: Stereoselective interaction of pantoprazole with ABCG2. II. In vitro flux analysis.
abstract: (-)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 K(M) 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 T(Max) compared with the (-)PAN for both rAbcg2 (7.86 versus 2.49 nmol/h · cm(2)) and ABCG2 (10.2 versus 3.29 nmol/h · cm(2)). Effective ABCG2 surface-area permeability of (-)PAN was 9920 and 5480 (μl/h)/cm(2) for rAbcg2 and ABCG2, respectively, compared with the (+)PAN isomer (4250 and 1920 μl/h · cm(2), 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536, USA.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Wang
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000737:chemistry* / Q000493:pharmacokinetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D002463:Cell Membrane Permeability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D013058:Mass Spectrometry; D008892:Milk / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000077402:Pantoprazole; D051381:Rats; D013237:Stereoisomerism; D014162:Transfection
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D009363:Neoplasm Proteins; D000077402:Pantoprazole