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 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.
Footnotes
This work was supported in part by the National Institutes of Health National Center for Research Resources [KL2-RR024154].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- MDCKII
- Madin-Darby canine kidney II
- ABCG2/Abcg2
- ATP binding cassette transporter family G member 2
- rAbcg2
- rat Abcg2
- PAN
- pantoprazole
- M/S
- milk to serum
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- HPLC
- high-performance liquid chromatography
- PObs
- observed permeability
- PSD
- permeability-surface area for passive diffusion
- PSPC
- permeability-surface area of paracellular transport
- PSAE
- permeability-surface area of active efflux mediated by ABCG2 on apical side
- ERα
- asymmetry efflux ratios
- PSAE,Eff
- effective apical efflux permeability
- B-to-A
- basolateral-to-apical
- A-to-B
- apical-to-basolateral.
- Received July 6, 2011.
- Accepted February 21, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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