Abstract
Active transport of drug into milk is a major concern in breastfeeding. Abcg2 plays a critical role in drug transfer into rat milk, which is consistent with evidence in humans. Although it is estimated that approximately half of all therapeutic agents are chiral, there have been few reports of stereoselective interactions with ABCG2. The purpose of this study was to investigate the interaction of pantoprazole (PAN) isomers with Abcg2 in in vitro and in vivo experiments. Pantoprazole isomer flux was characterized using Abcg2-Madin-Darby canine kidney II (MDCKII) cells in Transwell plates. In a crossover design, Sprague-Dawley lactating rats were used to study PAN accumulation in milk after an intravenous infusion of pantoprazole mixture in the presence/absence of Abcg2 inhibitor [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 (GF120918)]. Samples were analyzed by high-performance liquid chromatography/liquid chromatography-mass spectrometry. The results indicated that pantoprazole isomers were transported in an identical fashion in vector-MDCKII cell lines, whereas a significant difference in flux was observed in Abcg2-MDCKII cell line. The administration of GF120918 slightly increased the concentration of both isomers in serum, but no statistical difference was observed. However, the systemic clearance of (+)PAN (0.57 ± 0.1) was larger than (−)PAN (0.44 ± 0.12) (P < 0.01). Milk to serum ratio (M/S) of (−)PAN (1.36 ± 0.20) was 2.5-fold greater than that of (+)PAN (0.54 ± 0.09) (P < 0.01). Administration of GF120918 decreased M/S of (−)PAN to 0.50 ± 0.08 (P < 0.001) and (+)PAN to 0.38 ± 0.07 (P > 0.05). In conclusion, Abcg2, which is responsible for differential accumulation in milk, interacts stereoselectively with PAN isomers. Stereoselective transport of ABCG2 may have broader consequences in drug disposition.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- ABCG2
- ATP binding cassette transporter isoform G member 2
- PAN
- pantoprazole
- MDCK
- Madin-Darby canine kidney
- P-gp
- P-glycoprotein
- rAbcg2
- rat Abcg2
- 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
- LC-MS
- liquid chromatography-mass spectrometry
- DMSO
- dimethyl sulfoxide
- ERα
- asymmetrical efflux ratio
- M/S
- milk to serum ratio
- W/S
- whole to skim milk ratio.
- Received July 6, 2011.
- Accepted February 16, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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