title: The ABCG2 Efflux Transporter in the Mammary Gland Mediates Veterinary Drug Secretion across the Blood-Milk Barrier into Milk of Dairy Cows.
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.
authors.affiliation: 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.).
authors.forename: Hanna
authors.initials: H
authors.lastname: Mahnke
authors.affiliation: 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.).
authors.forename: Mariana
authors.initials: M
authors.lastname: Ballent
authors.affiliation: 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.).
authors.forename: Sven
authors.initials: S
authors.lastname: Baumann
authors.affiliation: 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.).
authors.forename: Fernanda
authors.initials: F
authors.lastname: Imperiale
authors.affiliation: 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.).
authors.forename: Martin
authors.initials: M
authors.lastname: von Bergen
authors.affiliation: 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.).
authors.forename: Carlos
authors.initials: C
authors.lastname: Lanusse
authors.affiliation: 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.).
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Lifschitz
authors.affiliation: 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.) honscha@vetmed.uni-leipzig.de.
authors.forename: Walther
authors.initials: W
authors.lastname: Honscha
authors.affiliation: 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.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Halwachs
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism; D001693:Biological Transport, Active / Q000502:physiology; D002417:Cattle; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D007774:Lactation / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008892:Milk / Q000378:metabolism*; D019155:Veterinary Drugs / Q000378:metabolism*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000900:Anti-Bacterial Agents; D019155:Veterinary Drugs