Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin.
Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in danofloxacin secretion into milk. In addition, the role of potential drug-drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1(-/-) mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of danofloxacin. However, the milk concentration and milk-to-plasma ratio of danofloxacin were almost twofold higher in wild-type compared with Bcrp1(-/-) mice. The in vivo interaction with ivermectin was studied in sheep after co-administration of danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of danofloxacin but significantly decreased danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug-drug interactions mediated by BCRP.
Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Universidad de León, León, Spain.
R
R
Real
E
E
Egido
M
M
Pérez
L
L
González-Lobato
B
B
Barrera
J G
JG
Prieto
A I
AI
Alvarez
G
G
Merino
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D000977:Antiparasitic Agents / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007559:Ivermectin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008892:Milk / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012756:Sheep
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000900:Anti-Bacterial Agents; D000977:Antiparasitic Agents; D024841:Fluoroquinolones; D009363:Neoplasm Proteins; C068581:danofloxacin; D007559:Ivermectin