The ABCG2 efflux transporter in the mammary gland mediates veterinary drug secretion across the blood-milk barrier into milk of dairy cows

In human and mice ATP-binding cassette efflux transporter ABCG2 represents themain 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. Comparedwith the parent drugMNP,we detected higherMNPSO2 plasma concentrations (expressed as area under the concentration-versustime curve). Moreover, we observed MNPSO₂ excretion into milk of dairy cows with a high milk-to-plasmaratio of 6.75. Inmechanistic flux assays, we determined a preferential time-dependent basolateral-toapical (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 anthelminticMNP represent substrates of the bovine mammary ABCG2 transporter and may thereby be actively concentrated in dairy milk.