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

MAHNKE, H; BALLENT, M.; BAUMANN, S; IMPERIALE, F.; VON BERGEN, M; LANUSSE, C.; LIFSCHITZ, A.L; HONSCHA, W.; HALWACHS, S

Drug Metabolism and Disposition

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Lugar: Baltimore; Año: 2016 vol. 44 p. 700 - 708

0090-9556

In human and miceATP-binding cassette efflux transporter ABCG2 represents the main route foractive drug transport into milk. However, there isno detailed information on the role of ABCG2 in drugsecretion and accumulation in milk of dairyanimals. We therefore examined ABCG2-mediated drugtransport in the bovine mammary gland by parallel pharmacokinetic studies inlactating Jersey cows and in vitro flux studiesusing the anthelmintic drug monepantel (MNP) asrepresentative bovine ABCG2 (bABCG2) drugsubstrate. Animals received MNP (Zolvix, Novartis Animal Health Inc.) once (2.5mg/kg per os) and the concentrations of MNP and the active MNP metabolite MNPSO2 were assessed byhigh-performance liquid chromatography. Compared with the parent drug MNP, we detected higher MNPSO2 plasmaconcentrations (expressed as area under the concentration-versus-time curve). Moreover,we observed MNPSO2 excretion into milk of dairy cows with a high milk-to-plasmaratio of 6.75. In mechanistic flux assays, we determined a preferential time-dependentbasolateral-to-apical (B > A) MNPSO2 transport across polarized Madin-Darbycanine kidney II cells-bABCG2 monolayers using liquid chromatography coupledwith tandem mass spectrometry analysis. The B > A MNPSO2 transport wassignificantly inhibited by the ABCG2 inhibitor fumitremorgin C in bABCG2- butnot in mock-transduced MDCKII cells. Additionally, the antibiotic drug enrofloxacin, the benzimidazole anthelminticoxfendazole and the macrocyclic lactoneanthelmintic moxidectin caused a reduction in the MNPSO2(B > A) net efflux. Altogether,this study indicated that therapeutically relevant drugs like the anthelminticMNP represent substrates of the bovine mammary ABCG2 transporter and may thereby be actively concentrated in dairy milk.