In vivo inhibition of BCRP/ABCG2 mediated transport of nitrofurantoin by the isoflavones genistein and daidzein: a comparative study in Bcrp1 (-/-) mice.
OBJECTIVE
The aim of this study was to determine in vivo inhibition by the isoflavones genistein and daidzein of nitrofurantoin (NTF), a well-known substrate of the ABC transporter BCRP/ABCG2.


METHODS
MDCKII cells and their human BCRP- and murine Bcrp1-transduced subclones were used to establish inhibition in transepithelial transport assays. Bcrp1(-/-) and wild-type mice were coadministered with nitrofurantoin (20 mg/kg) and a mixture of genistein (100 mg/kg) and daidzein (100 mg/kg).


RESULTS
Transepithelial NFT transport was inhibited by the isoflavones. Plasma concentration of NTF at 30 min was 1.7-fold higher (p ≤ 0.05) in wild-type mice after isoflavone administration. AUC values were not significantly different. BCRP/ABCG2-mediated secretion into milk was inhibited since milk/plasma ratios were lower in wild-type mice with isoflavones (7.1 ± 4.2 vs 4.2 ± 1.6, p ≤ 0.05). NTF bile levels were significantly decreased by isoflavone administration in wild-type animals (8.8 ± 3.4 μg/ml with isoflavones vs 3.7 ± 3.3 μg/ml without isoflavones).


CONCLUSIONS
Our data showed that in vivo interaction of high doses of soy isoflavones with BCRP substrates may affect plasma levels but the main effect occurs in specific target organs, in our case, liver and mammary glands.
Merino
Gracia
G
Instituto de Sanidad Animal y Desarrollo Ganadero, Universidad de León, León, Spain.
Perez
Miriam
M
Real
Rebeca
R
Egido
Estefania
E
Prieto
Julio G
JG
Alvarez
Ana I
AI
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000097:blood / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D001692:Biological Transport / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D007774:Lactation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009582:Nitrofurantoin / Q000097:blood / Q000493:pharmacokinetics*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000892:Anti-Infective Agents, Urinary; D007529:Isoflavones; D009363:Neoplasm Proteins; C004742:daidzein; D009582:Nitrofurantoin; D019833:Genistein