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Research ArticleArticle

The ABCG2 Efflux Transporter in the Mammary Gland Mediates Veterinary Drug Secretion across the Blood-Milk Barrier into Milk of Dairy Cows

Hanna Mahnke, Mariana Ballent, Sven Baumann, Fernanda Imperiale, Martin von Bergen, Carlos Lanusse, Adrian L. Lifschitz, Walther Honscha and Sandra Halwachs
Drug Metabolism and Disposition May 2016, 44 (5) 700-708; DOI: https://doi.org/10.1124/dmd.115.068940
Hanna Mahnke
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Mariana Ballent
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Sven Baumann
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Fernanda Imperiale
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Martin von Bergen
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Carlos Lanusse
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Adrian L. Lifschitz
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Walther Honscha
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Sandra Halwachs
Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine (H.M., W.H., S.H.), Institute of Pharmacy, Faculty of Biosciences, Pharmacy and Psychology (S.B.), University of Leipzig, Leipzig, Germany; Laboratorio de Farmacología, Centro de Investigacion Veterinaria de Tandil, (CIVETAN, CONICET-CICPBA), Facultad de Cs. Veterinarias, UNCPBA, Tandil, Argentina (M.B., F.I., C.L., A.L.L.); Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany (S.B., M.vB.); Department of Chemistry and Bioscience, Center for Microbial Communities, University of Aalborg, Aalborg, Denmark (M.vB.)
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Abstract

In human and mice ATP-binding cassette efflux transporter ABCG2 represents the main route for active drug transport into milk. However, there is no detailed information on the role of ABCG2 in drug secretion and accumulation in milk of dairy animals. We therefore examined ABCG2-mediated drug transport in the bovine mammary gland by parallel pharmacokinetic studies in lactating Jersey cows and in vitro flux studies using the anthelmintic drug monepantel (MNP) as representative bovine ABCG2 (bABCG2) drug substrate. Animals received MNP (Zolvix, Novartis Animal Health Inc.) once (2.5 mg/kg per os) and the concentrations of MNP and the active MNP metabolite MNPSO2 were assessed by high-performance liquid chromatography. Compared with the parent drug MNP, we detected higher MNPSO2 plasma concentrations (expressed as area under the concentration-versus-time curve). Moreover, we observed MNPSO2 excretion into milk of dairy cows with a high milk-to-plasma ratio of 6.75. In mechanistic flux assays, we determined a preferential time-dependent basolateral-to-apical (B > A) MNPSO2 transport across polarized Madin-Darby canine kidney II cells–bABCG2 monolayers using liquid chromatography coupled with tandem mass spectrometry analysis. The B > A MNPSO2 transport was significantly inhibited by the ABCG2 inhibitor fumitremorgin C in bABCG2- but not in mock-transduced MDCKII cells. Additionally, the antibiotic drug enrofloxacin, the benzimidazole anthelmintic oxfendazole and the macrocyclic lactone anthelmintic moxidectin caused a reduction in the MNPSO2 (B > A) net efflux. Altogether, this study indicated that therapeutically relevant drugs like the anthelmintic MNP represent substrates of the bovine mammary ABCG2 transporter and may thereby be actively concentrated in dairy milk.

Footnotes

    • Received December 11, 2015.
    • Accepted March 7, 2016.
  • This work was supported by the German Research Foundation (DFG) [Grant no. HA 7159/1-1] and by the National Council of Scientific and Technical Research [CONICET; Argentina PCI Res. 3060/13].

  • dx.doi.org/10.1124/dmd.115.068940.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (5)
Drug Metabolism and Disposition
Vol. 44, Issue 5
1 May 2016
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Research ArticleArticle

Drug Transport across the Bovine Blood-Milk Barrier by ABCG2

Hanna Mahnke, Mariana Ballent, Sven Baumann, Fernanda Imperiale, Martin von Bergen, Carlos Lanusse, Adrian L. Lifschitz, Walther Honscha and Sandra Halwachs
Drug Metabolism and Disposition May 1, 2016, 44 (5) 700-708; DOI: https://doi.org/10.1124/dmd.115.068940

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Research ArticleArticle

Drug Transport across the Bovine Blood-Milk Barrier by ABCG2

Hanna Mahnke, Mariana Ballent, Sven Baumann, Fernanda Imperiale, Martin von Bergen, Carlos Lanusse, Adrian L. Lifschitz, Walther Honscha and Sandra Halwachs
Drug Metabolism and Disposition May 1, 2016, 44 (5) 700-708; DOI: https://doi.org/10.1124/dmd.115.068940
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