Short communication: The gain-of-function Y581S polymorphism of the ABCG2 transporter increases secretion into milk of danofloxacin at the therapeutic dose for mastitis treatment

Abstract

The ATP-binding cassette transporter ABCG2 restricts the exposure of certain drugs and natural compounds in different tissues and organs. Its expression in the mammary gland is induced during lactation and is responsible for the active secretion of many compounds into milk, including antimicrobial agents. This particular function of ABCG2 may affect drug efficacy against mastitis and the potential presence of drug residues in the milk. Previous in vitro and in vivo studies showed increased transport of several compounds, including fluoroquinolones, by the bovine ABCG2 Y581S polymorphism. Our main purpose was to study the potential effect of this bovine ABCG2 polymorphism on the secretion into milk of the antimicrobial danofloxacin administered at the therapeutic dose of 6mg/kg used for mastitis treatment. In addition, the effect of this polymorphism on the relative mRNA and protein levels of ABCG2 by quantitative real-time PCR and Western blot were studied. Danofloxacin 18% (6mg/kg) was administered to 6 Y/Y homozygous and 5 Y/S heterozygous cows. Danofloxacin levels in milk and milk-to-plasma concentration ratios were almost 1.5- and 2-fold higher, respectively, in Y/S cows compared with the Y/Y cows, showing a higher capacity of this variant to transport danofloxacin into milk. Furthermore, the higher activity of this polymorphism is not linked to higher ABCG2 mRNA or protein levels. These results demonstrate the relevant effect of the Y581S polymorphism of the bovine ABCG2 transporter in the secretion into milk of danofloxacin after administration of 6mg/kg, with potentially important consequences for mastitis treatment and for milk residue handling.

Effect of bovine ABCG2 polymorphism Y581S SNP on secretion into milk of enterolactone, riboflavin and uric acid

“…In this study, we examine the relevance of the Y581S polymorphism on the transport of endogenous and dietary compounds present in cow milk as previously reported for milk secretion of fluoroquinolone drugs such as danofloxacin 2015).…”

“…Moreover, milk/plasma ratio was much higher in Y/S cows (2.99 ± 0.46) than in Y/Y cows (1.44 ± 0.50), which corroborated the in vitro results obtained with the S581 variant. The Y581S SNP of the bovine ABCG2 can affect the plasma concentration of several substrates (Otero et al, 2015). We hypothesize that the decrease in plasma disposition of specific substrates of ABCG2 in Y/S cows is probably due to the enhanced function of the Y581S polymorphism.…”

“…The overall lactation period was mid-late. Animals were genotyped for the Y581S polymorphism of the bovine ABCG2 transporter (Otero et al, 2015) and grouped into five Y/S heterozygous cows and six Y/Y homozygous cows. Milk and plasma sampling was performed on the private Garfi SAT farm located at Santa María del Monte del Condado (Leon, Spain).…”

“…Y581S SNP frequency can reach 20% in some Holstein populations (Ron et al, 2006). Moreover, this SNP has been described in vitro as a gain-of-function polymorphism revealing a higher capacity of the Y581S variant (Real et al, 2011) that produces a higher in vivo transport of antimicrobials such as danofloxacin into milk 2015). The involvement of ABCG2 in milk secretion and plasma levels of endogenous compounds has been extensively studied in humans.…”

Alterations in the Rumen Liquid-, Particle- and Epithelium-Associated Microbiota of Dairy Cows during the Transition from a Silage- and Concentrate-Based Ration to Pasture in Spring

“…The adaptability of rumen microbiota is a key feature of ruminant physiology and survival strategy (Russell and Rychlik, 2001; McCann et al, 2014a; Zanton, 2015). It has been shown that whenever cows undergo a ration change rumen microbiota needs between 1 day and sometimes even longer than 3 weeks to adapt and stabilize, depending on the group of bacteria, archaea, fungi, or protozoa, the extent of diet change and the behavioral adaptation required (Hackmann, 2015). de Menezes et al (2011) have shown in a cross-over design, with 2 weeks for diet adaptation, that the liquid and solid rumen bacterial and archaeal community of TMR and pasture fed dairy cows differs significantly.…”