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The ATP-binding cassette transporter G2 (ABCG2) is an efflux protein involved in the bioavailability and secretion into milk of several compounds including anti-inflammatory drugs. The aim of this work was to determine the effect in sheep of an ABCG2 inhibitor, such as the macrocyclic lactone ivermectin, on the secretion into milk of meloxicam, a non-steroidal anti-inflammatory drug widely used in veterinary medicine, and recently reported as an ABCG2 substrate. In vitro meloxicam transport assays in ovine ABCG2-transduced cells have shown that ivermectin is an efficient inhibitor of in vitro transport of meloxicam mediated by ovine ABCG2, with a 75% inhibition in the transport ratio (24.85 ± 4.62 in controls vs 6.31 ± 1.37 in presence of ivermectin). In addition, the role of ovine ABCG2 in secretion into milk of meloxicam was corroborated using Assaf lactating sheep coadministered with ivermectin. Animals were administered subcutaneously with meloxicam (0.5 mg/kg) with or without ivermectin (0.2 mg/kg). No difference in plasma pharmacokinetic parameters was found between treatments. In the case of milk, a significant reduction in the area under concentration-time curve (AUC) (3.92 ± 0.66 vs 2.26 ± 1.52 μg·h/mL) and the AUC milk-to-plasma ratio (0.17 ± 0.03 vs 0.09 ± 0.06) was reported for ivermectin-treated animals compared to controls., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Albendazole (ABZ) is an anthelmintic with a broad-spectrum activity, widely used in human and veterinary medicine. ABZ is metabolized in all mammalian species to albendazole sulfoxide (ABZSO), albendazole sulfone (ABZSO 2 ) and albendazole 2-aminosulphone (ABZSO 2 -NH 2 ). ABZSO and ABZSO 2 are the main metabolites detected in plasma and all three are detected in milk. The ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter that is involved in the active secretion of several compounds into milk. Previous studies have reported that ABZSO was in vitro transported by ABCG2. The aim of this work is to correlate the in vitro interaction between ABCG2 and the other ABZ metabolites with their secretion into milk by this transporter. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we show that ABZSO 2 and ABZSO 2 -NH 2 are in vitro substrates of both. In vivo assays carried out with wild-type and Abcg2 -/- lactating female mice demonstrated that secretion into milk of these ABZ metabolites was mediated by Abcg2. Milk concentrations and milk-to-plasma ratio were higher in wild-type compared to Abcg2 -/- mice for all the metabolites tested. We conclude that ABZ metabolites are undoubtedly in vitro substrates of ABCG2 and actively secreted into milk by ABCG2.

ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several compounds in milk. The in vitro and in vivo interactions between tryptophan-related compounds and ABCG2 were investigated. The tryptophan metabolome was determined by liquid chromatography-tandem mass spectrometry in milk and plasma from wild-type and Abcg2 -/- mice as well as dairy cows carrying the ABCG2 Y581S polymorphism (Y/S) and noncarrier animals (Y/Y). The milk-to-plasma ratios of tryptophan, kynurenic acid, kynurenine, anthranilic acid, and xanthurenic acid were higher in wild-type mice than in Abcg2 -/- mice. The ratio was 2-fold higher in Y/S than in Y/Y cows for kynurenine. In vitro transport assays confirmed that some of these compounds were in vitro substrates of the transporter and validated the differences observed between the two variants of the bovine protein. These findings show that the secretion of metabolites belonging to the kynurenine pathway into milk is mediated by ABCG2., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Therapeutic outcome results of the coadministration of several drugs in veterinary medicine is affected by, among others, the relationship between drugs and ATP-binding cassette (ABC) transporters, such as ABCG2. ABCG2 is an efflux protein involved in the bioavailability and milk secretion of drugs. The aim of this work was to determine the role of eprinomectin, a macrocyclic lactone (ML) member of avermectin class, as inhibitor of ABCG2. The experiments were carried out through in vitro inhibition assays based on mitoxantrone accumulation and transport assays in ovine ABCG2 transduced cells using the antimicrobial drug danofloxacin and the anti-inflammatory drug meloxicam, both widely used in veterinary medicine and well known ABCG2 substrates. The inhibition results obtained showed that eprinomectin was an efficient in vitro ABCG2 inhibitor, tested in mitoxantrone accumulation assays. In addition, this ML decreased ovine ABCG2-mediated transport of danofloxacin and meloxicam. To evaluate the role of eprinomectin in systemic exposure of drugs, pharmacokinetic assays based on subcutaneous coadministration of eprinomectin with danofloxacin (1.25 mg/kg) or meloxicam (0.5 mg/kg) in sheep were performed obtaining a significant increase of systemic exposure of these drugs. Especially relevant was the increase of the systemic concentration of meloxicam, since coadministration with eprinomectin increased significantly the plasma concentration of meloxicam, obtaining an increase of AUC (0-72 h) value of more than 40%., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2 -/- mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg·h/ml versus 73.80 ± 10.00 µg·h/ml). Differences in meloxicam distribution were reported for several tissues after oral and intravenous administration, with a 20-fold higher concentration in the brain of Abcg2 -/- after oral administration. Meloxicam secretion into milk was also affected by the transporter, with a 2-fold higher milk-to-plasma ratio in wild-type compared with Abcg2 -/- lactating female mice after oral and intravenous administration. We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID) widely used in veterinary medicine. It is indicated to treat inflammatory processes, pain, and pyrexia in farm animals. In addition, it is one of the few NSAIDs approved for use in dairy cows, and consequently gives rise to concern regarding its milk residues. The ABCG2 efflux transporter is induced during lactation in the mammary gland and plays an important role in the secretion of different compounds into milk. Previous reports have demonstrated that bovine ABCG2 Y581S polymorphism increases fluoroquinolone levels in cow milk. However, the implication of this transporter in the secretion into milk of anti-inflammatory drugs has not yet been studied. The objective of this work was to study the role of ABCG2 in the secretion into milk of flunixin and its main metabolite, 5-hydroxyflunixin, using Abcg2 (-/-) mice, and to investigate the implication of the Y581S polymorphism in the secretion of these compounds into cow milk. Correlation with the in vitro situation was assessed by in vitro transport assays using Madin-Darby canine kidney II cells overexpressing murine and the two variants of the bovine transporter. Our results show that flunixin and 5-hydroxyflunixin are transported by ABCG2 and that this protein is responsible for their secretion into milk. Moreover, the Y581S polymorphism increases flunixin concentration into cow milk, but it does not affect milk secretion of 5-hydroxyflunixin. This result correlates with the differences in the in vitro transport of flunixin between the two bovine variants. These findings are relevant to the therapeutics of anti-inflammatory drugs., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)