Role of ABCG2 in Secretion into Milk of the Anti-Inflammatory Flunixin and Its Main Metabolite: In Vitro-In Vivo Correlation in Mice and Cows

Abstract

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.

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

“…4). This difference is similar to the values obtained previously in our group for another substrate belonging to the NSAID family, flunixin [20]. NSAID transport in the mammary gland can have clinical, toxicological and nutritional implications.…”

“…Furthermore, ABCG2 is also involved in the distribution and elimination of diclofenac glucuronides in mice [19]. Recent studies have demonstrated that ABCG2 is involved in the secretion of flunixin and its main metabolite, 5OH-flunixin, into milk [20]. Although meloxicam is a widely used drug in the medical and veterinary field, there are no studies of its interaction with ABC transporters which might influence its drug pharmacokinetics.…”

Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk

“…Danofloxacin, enrofloxacin and ciprofloxacin are also effluxed into milk by bovine ABCG2 more efficiently in polymorphic Y581S than in wild-type cows [151,152,169]. After administration of flunixin to dairy cows, both the parental drug and its metabolite 5-hydroxyflunixin were secreted into milk and in the case of flunixin, its secretion was increased in carriers of the polymorphism Y581S compared to wild-type cows [141].…”

“…Although some of these drugs, such as diclofenac, are in vitro substrates of ABCG2 [140], there is no information about the specific involvement of this transporter in its secretion into milk. Until now, flunixin and its metabolite 5-hydroxyflunixin are the only NSAIDs which have been shown to be transferred into milk by murine and bovine ABCG2 in vivo [141].…”

“…According to this hypothesis, some studies revealed that milk concentration of flunixin and 5OH-flunixin after oral administration of the drug was different in dairy cows with mastitis compared to healthy controls [207,208]. Since both compounds have been described as bovine ABCG2 substrates [141], the differential transport may be due to potential transporter expression changes observed during infection [206]. Interestingly, not only pathogenic microorganisms but also microbiome can affect the expression of transporters.…”