title: 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.
authors.affiliation: Department of Biomedical Sciences-Physiology, Veterinary Faculty, University of Leon, Campus de Vegazana 24071, Leon, Spain; Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana 24071, Leon, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Otero
authors.affiliation: Department of Biomedical Sciences-Physiology, Veterinary Faculty, University of Leon, Campus de Vegazana 24071, Leon, Spain; Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana 24071, Leon, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Barrera
authors.affiliation: Department of Biomedical Sciences-Physiology, Veterinary Faculty, University of Leon, Campus de Vegazana 24071, Leon, Spain.
authors.forename: A
authors.initials: A
authors.lastname: de la Fuente
authors.affiliation: Department of Biomedical Sciences-Physiology, Veterinary Faculty, University of Leon, Campus de Vegazana 24071, Leon, Spain; Instituto de Biomedicina (IBIOMED), University of Leon, Campus de Vegazana 24071, Leon, Spain.
authors.forename: J G
authors.initials: JG
authors.lastname: Prieto
authors.affiliation: Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana 24071, Leon, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Marqués
authors.affiliation: Department of Biomedical Sciences-Physiology, Veterinary Faculty, University of Leon, Campus de Vegazana 24071, Leon, Spain.
authors.forename: A I
authors.initials: AI
authors.lastname: Álvarez
authors.affiliation: Department of Biomedical Sciences-Physiology, Veterinary Faculty, University of Leon, Campus de Vegazana 24071, Leon, Spain; Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), University of Leon, Campus de Vegazana 24071, Leon, Spain. Electronic address: gmerp@unileon.es.
authors.forename: G
authors.initials: G
authors.lastname: Merino
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002417:Cattle / Q000235:genetics / Q000502:physiology*; D004350:Drug Residues; D005260:Female; D024841:Fluoroquinolones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006720:Homozygote; D007774:Lactation; D008414:Mastitis, Bovine / Q000188:drug therapy / Q000378:metabolism*; D008892:Milk / Q000737:chemistry; D011110:Polymorphism, Genetic
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; C068581:danofloxacin
keywords: ABCG2; danofloxacin; milk secretion; polymorphism