Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: effect on plasma and milk levels of danofloxacin in sheep.
Danofloxacin is a synthetic fluoroquinolone antibacterial agent and a substrate for ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). This protein actively extrudes drugs from cells in the intestine, liver, kidney, and other organs, such as the mammary gland. The purpose of this study was to determine whether genistein and daidzein, isoflavones present in soy and known inhibitors of ABCG2, could diminish danofloxacin secretion into milk. The results obtained from BCRP-transduced MDCK-II cells (Mardin-Darby canine kidney) showed that both isoflavones efficiently inhibited the in vitro transport of the drug. In addition, danofloxacin transport into milk was studied in Assaf sheep. The experimental design with ewes (n = 18) included ewes fed with standard forage, soy-enriched forage for 15 days prior to the experiment or standard forage paired with orally administered exogenous genistein and daidzein. The danofloxacin levels in the milk of ewes in the soy-enriched diet group were decreased. The area under concentration-time curve AUC (0-24 h) was 9.3 ± 4.6 vs. 16.58 ± 4.44 μgh/mL in the standard forage or control group. The plasma levels of danofloxacin were unmodified. The AUC (0-24 h) milk/plasma ratio decreased by over 50% in the soy-enriched diet group, compared to the control group (4.90 ± 2.65 vs. 9.58 ± 2.17). Exogenous administration of isoflavones did not modify danofloxacin secretion into milk. This study showed that milk excretion of a specific substrate of BCRP, such as danofloxacin, can be diminished by the presence of isoflavones in the diet.
Departamento de Ciencias Biomédicas-Fisiología, Facultad de Veterinaria, Campus de Vegazana s/n, Universidad de León, León, Spain.
Miriam
M
Perez
Jon A
JA
Otero
Borja
B
Barrera
Julio G
JG
Prieto
Gracia
G
Merino
Ana I
AI
Alvarez
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D002460:Cell Line; D004285:Dogs; D004347:Drug Interactions; D024841:Fluoroquinolones / Q000097:blood / Q000493:pharmacokinetics*; D005786:Gene Expression Regulation; D019833:Genistein / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007529:Isoflavones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008892:Milk / Q000737:chemistry*; D012756:Sheep / Q000097:blood*; D013025:Glycine max
D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D007529:Isoflavones; C068581:danofloxacin; C004742:daidzein; D019833:Genistein