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.

Pharmacokinetic assessment of the monepantel plus oxfendazole combined administration in dairy cows

“…The milk‐to‐plasma ratio may allow the prediction of potential active BCRP‐mediated drug secretion and, in consequence, residual accumulation of BCRP substrates into milk (Alvarez et al., ). Therefore, the current data corroborate results recently obtained by in vitro BCRP flux studies (Mahnke et al., ) showing active BCRP‐mediated secretion of MNPSO 2 .…”

“…Pharmacokinetic data obtained from MNP Group have been reported by Mahnke et al. (). MNP concentrations were only detected during a short period.…”

“…The interaction of MNP and MNPSO 2 with ruminant BCRP was shown (Halwachs, Wassermann, & Honscha, ). Moreover, BCRP‐mediated transport of the main active MNP metabolite MNPSO 2 was demonstrated by flux studies using polarized MDCKII‐bABCG2 monolayers (Mahnke et al., ). As the concomitant drug administration may induce drug‐drug interactions affecting both pharmacokinetics and drug accumulation into milk, the present study aimed to investigate the effect of combined treatment of the novel anthelmintic drug MNP with the benzimidazole anthelmintic OFZ on both plasma and milk concentrations in lactating dairy cows.…”

“…Benzimidazole methylcarbamates, such as albendazole sulphoxide (ABZSO) and OFZ, have been reported to interact with BCRP in vitro (Merino et al., ). Moreover, OFZ showed an inhibitory effect on efflux activity in MDCKII‐BCRP cell monolayers, with an apparent higher potency compared with their respective thioethers, albendazole and flubendazole (Mahnke et al., ). In fact, these authors also corroborated that OFZ reduces the in vitro MNPSO 2 net efflux mediated by BCRP in MDCKII‐bABCG2 cells (Mahnke et al., ).…”

“…Moreover, OFZ showed an inhibitory effect on efflux activity in MDCKII‐BCRP cell monolayers, with an apparent higher potency compared with their respective thioethers, albendazole and flubendazole (Mahnke et al., ). In fact, these authors also corroborated that OFZ reduces the in vitro MNPSO 2 net efflux mediated by BCRP in MDCKII‐bABCG2 cells (Mahnke et al., ). Thus, for drugs exhibiting a high secretion rate into milk as it was observed for MNPSO 2 , the administration of MNP parent drug in combination with other BCRP substrates such as OFZ may modify the drug excretion pattern into milk.…”