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 (2/2) 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.

The ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several drugs into milk. The bovine Y581S ABCG2 polymorphism increases the secretion into milk of the fluoroquinolone danofloxacin in Holstein cows. Danofloxacin and enrofloxacin are the fluoroquinolones most widely used in veterinary medicine. Both enrofloxacin (ENRO) and its active metabolite ciprofloxacin (CIPRO) reach milk at relatively high concentrations. The aim of this work was to study the effect of the bovine Y581S ABCG2 polymorphism on in vitro transport as well as on concentrations in plasma and in milk of ENRO and CIPRO. Experiments using cells overexpressing bovine ABCG2 showed the effects of ABCG2 on the transport of CIPRO, demonstrating more efficient in vitro transport of this antimicrobial by the S581 variant as compared with the Y581 variant. Animal studies administering 2.5mg/kg of ENRO subcutaneously to Y/Y 581 and Y/S 581 cows revealed that concentrations in plasma of ENRO and CIPRO were significantly lower in Y/S animals. Regardless of the genotype, the antimicrobial profile in milk after the administration of ENRO was predominantly of CIPRO. With respect to the genotype effects on the amounts of drugs present in milk, AUC0-24 values were more than 1.2 times higher in Y/S cows for ENRO and 2.2 times for CIPRO, indicating a greater capacity of Y581S to transfer these drugs into milk. These results emphasize the clinical relevance of this polymorphism as a factor affecting the concentrations in plasma and in milk of drugs of importance in veterinary medicine.

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BackgroundFlaxseed is the most common and rich dietary source of lignans and is an acceptable supply of energy for livestock. Flaxseed lignans are precursors of enterolignans, mainly enterolactone and enterodiol, produced by the rumen and intestinal microbiota of mammals and have many important biological properties as phytoestrogens. Potential food-drug interactions involving flaxseed may be relevant for veterinary therapy, and for the quality and safety of milk and dairy products. Our aim was to investigate a potential food-drug interaction involving flaxseed, to explore whether the inclusion of flaxseed in sheep diet affects concentration of the antimicrobial danofloxacin in milk.ResultsIncreased concentrations of enterodiol and enterolactone were observed in sheep plasma and milk after 2 weeks of flaxseed supplementation (P < 0.05). However, enterolactone and enterodiol conjugates were not detected in milk. Milk danofloxacin pharmacokinetics showed that area under the curve (AUC)0–24, maximum concentration (Cmax) and AUC0–24 milk-to-plasma ratios were reduced by 25–30% in sheep fed flaxseed-enriched diets (P < 0.05). Our results demonstrate, therefore, that flaxseed-enriched diets reduce the amount of danofloxacin in sheep milk and enrich the milk content of lignan-derivatives.ConclusionThese findings highlight an effect of flaxseed-enriched diets on the concentration of antimicrobials in ruminant’s milk, revealing the potential of these modified diets for the control of residues of antimicrobial drugs in milk.