The Bovine ATP-Binding Cassette Transporter ABCG2 Tyr581Ser Single-Nucleotide Polymorphism Increases Milk Secretion of the Fluoroquinolone Danofloxacin

Abstract

The bovine adenosine triphosphate-binding cassette transporter G2 (ABCG2/breast cancer resistance protein) polymorphism Tyr581Ser (Y581S) has recently been shown to increase in vitro transepithelial transport of antibiotics. Since this transporter has been extensively related to the active secretion of drugs into milk, the potential in vivo effect of this polymorphism on secretion of xenobiotics in livestock could have striking consequences for milk production, the dairy industry, and public health. Our purpose was to study the in vivo effect of this polymorphism on the secretion of danofloxacin, a widely used veterinary antibiotic, into milk. Danofloxacin (1.25 mg/kg) was administered to six Y/Y 581 homozygous and six Y/S 581 heterozygous lactating cows, and plasma and milk samples were collected and analyzed by high-performance liquid chromatography. No differences were found in the pharmacokinetic parameters of danofloxacin in plasma between the two groups of animals. In contrast, Y/S heterozygous cows showed a 2-fold increase in danofloxacin levels in milk. In addition, the pharmacokinetic elimination parameters, mean residence time and elimination half-life, were significantly lower in the milk of the animals carrying the Y/S polymorphism. These in vivo results are in agreement with our previously published in vitro data, which showed a greater capacity of the S581 variant in accumulation assays, and demonstrate, for the first time, an important effect of the Y581S single-nucleotide polymorphism on antibiotic secretion into cow milk. These findings could be extended to other ABCG2 substrates, and may be relevant for the treatment of mastitis and for the design of accurate and novel strategies to handle milk residues. IntroductionThe ATP-binding cassette (ABC) transporter ABCG2 (breast cancer resistance protein) is expressed in a wide range of tissues and organs, including the intestine, liver, blood-brain barrier, and mammary gland (van Herwaarden and Schinkel, 2006). It affects the bioavailability of its substrates and mediates the active secretion of xenobiotics and several vitamins in milk (van Herwaarden et al., 2007). The occurrence of drug residues in milk could lead to the development of bacterial resistance, allergies, or hypersensitivity reactions in consumers (McManaman and Neville, 2003). On the other hand, effective treatments for mastitis may require a considerable transfer of drugs into milk (Escudero et al., 2007). All of these issues are of great concern for general public health, the dairy industry, and veterinary therapeutics. Hence, identification of relevant factors for the transfer of drugs into milk in livestock constitutes a priority.Changes in the expression and/or the function of ABCG2 can lead to dramatic variations in the pharmacokinetics and secretion of its substrates into milk Ni et al., 2010). Several single-nucleotide polymorphisms (SNPs) have been studied in human ABCG2, and of these, Gln141Lys (Q141K) is one of the most important, causing impaired urate transport wh...

Role of ABCG2 in Transport of the Mammalian Lignan Enterolactone and its Secretion into Milk in Abcg2 Knockout Mice

“…In addition, mean plasma concentrations of endogenous enterolactone in wild-type mice (57 6 13 nM) (Table 1) were in agreement with the values reported in humans (Kuijsten et al, 2005;Adolphe et al, 2010). Recently, the secretion of compounds into ruminant milk has been reported to be affected by ABCG2 polymorphisms and ABCG2 inhibition by drugs and flavonoids (Real et al, 2011;Otero et al, 2013). Thus, these ABCG2-related factors presumably could affect enterolactone concentrations in milk and thus the possible health benefits of lignans from the consumption of milk.…”

Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: Role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter

“…4), with no evidence of interaction. Several reports showed a lack of ABCG2-mediated effect in plasma levels of danofloxacin, whereas milk levels of this antibiotic are widely affected by ABCG2 activity (Real et al, 2011a;Otero et al, 2013). However, in the present study, the low concentrations of TCBZ metabolites in milk prevented ABCG2-mediated interaction with danofloxacin.…”

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

“…This effect is similar to the one reported by Otero et al (2013) after the administration of danofloxacin at 1.25 mg/ kg with a 2-fold difference observed in the AUC milkto-plasma ratios between both genotypes. Our results show that the Y581S SNP in ABCG2 also increases the secretion into milk of danofloxacin administered at 6 mg/kg (18% solution).…”

“…Later on, we presented this SNP as an in vitro gain-of-function polymorphism, revealing a higher capacity of the Y581S variant to transport antimicrobials Real et al, 2011b). These data were recently corroborated in vivo, showing that cows carrying the Y581S polymorphism resulted in a 2-fold increase in milk levels of danofloxacin administered at 1.25 mg/kg (2.5% formulation; Otero et al, 2013). However, a formulation of danofloxacin 18% was recently developed to allow the delivery of a higher dose (6 mg/kg).…”