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Research ArticleArticle

Stereoselective Interaction of Pantoprazole with ABCG2. I. Drug Accumulation in Rat Milk

Lipeng Wang and Patrick J. McNamara
Drug Metabolism and Disposition May 2012, 40 (5) 1018-1023; DOI: https://doi.org/10.1124/dmd.111.041608
Lipeng Wang
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Patrick J. McNamara
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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.

    http://dx.doi.org/10.1124/dmd.111.041608.

  • 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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Drug Metabolism and Disposition: 40 (5)
Drug Metabolism and Disposition
Vol. 40, Issue 5
1 May 2012
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Research ArticleArticle

PANTOPRAZOLE STEREOSELECTIVE INTERACTION WITH Abcg2 IN VIVO

Lipeng Wang and Patrick J. McNamara
Drug Metabolism and Disposition May 1, 2012, 40 (5) 1018-1023; DOI: https://doi.org/10.1124/dmd.111.041608

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Research ArticleArticle

PANTOPRAZOLE STEREOSELECTIVE INTERACTION WITH Abcg2 IN VIVO

Lipeng Wang and Patrick J. McNamara
Drug Metabolism and Disposition May 1, 2012, 40 (5) 1018-1023; DOI: https://doi.org/10.1124/dmd.111.041608
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