Milk secretion of nitrofurantoin, as a specific BCRP/ABCG2 substrate, in assaf sheep: modulation by isoflavones¹

Abstract

Studies on residues in milk used for human consumption have increased due to health concerns and priority interest in the control of potentially risky drugs. The protein BCRP/ABCG2, present in the mammary epithelia, actively extrudes drugs into milk and can be modulated by isoflavones. Nitrofurantoin is a specific BCRP substrate which is actively excreted into milk by this transporter. In this research, we studied nitrofurantoin transport into milk in four experimental groups: G1-calves fed forage with isoflavones; G2-calves fed forage with isoflavones and administered exogenous genistein and daidzein; G3-calves fed forage without isoflavones; G4-calves fed forage without isoflavones and administered exogenous genistein and daidzein. Results show increased levels of nitrofurantoin in milk from calves without isoflavones (G3) and decreased nitrofurantoin residues in milk when isoflavones were present, either by forage (G1 and G2) or by exogenous administration (G4). The values of C(max) in milk were significantly lower in those groups with isoflavones in forage (G1, G2). Plasma levels were low and unmodified among the groups. Inter-individual variation was high. All these results seem to point to a feasible control of drug secretion into milk through isoflavones in the diet when the drug is a good BCRP/ABCG2 substrate.

In Vivo Inhibition of BCRP/ABCG2 Mediated Transport of Nitrofurantoin by the Isoflavones Genistein and Daidzein: A Comparative Study in Bcrp1 −/− Mice

“…Our results, in agreement with those previously published, showed a large difference in the concentration of nitrofurantoin into milk between wild-type and Bcrp1 −/− (9-fold higher in the wild-type mice), but we also observed a significant difference between wild-type animals with or without isoflavones, the excretion of NTF into milk being reduced two-fold. These results agree with our preliminary results obtained from lactating sheep (22,32), thus confirming that when a drug is a specific substrate of BCRP, milk secretion can be modulated by these isoflavones.…”

“…A novel recent study on the effect of flavonoid chrysin on nitrofurantoin pharmacokinetics showed that this interaction occurs in rats but not in mice possibly due to the higher levels of BCRP in the small intestine in rats compared with mice (21). We obtained positive results regarding the role of exogenous isoflavones' administration in milk secretion of nitrofurantoin in ewes, but interindividual variation made the interpretation of results difficult (22).…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Bcrp/BCRP is almost exclusively expressed on the apical surface of epithelial cells, including hepatocytes, proximal tubules, enterocytes, trophoblasts, yolk sac, and mammary glands as well as brain and retinal capillary endothelial cells (Table 8) (Maliepaard et al, 2001;Cooray et al, 2002;Jonker et al, 2002;Aronica et al, 2005;Tachikawa et al, 2005;Asashima et al, 2006;Fetsch et al, 2006;Pulido et al, 2006;Aleksunes et al, 2008b;Roberts et al, 2008). Expression of Bcrp/BCRP on lactating mammary glands in a number of species contributes to the excretion of chemicals into breast milk van Herwaarden et al, 2006Pérez et al, 2009).…”

The Anthelmintic Triclabendazole and Its Metabolites Inhibit the Membrane Transporter ABCG2/BCRP

“…Several studies have managed to increase the bioavailability and milk secretion of antibacterial agents, such as nitrofurantoin, or antitumorals, such as topotecan, or to improve brain penetration of the antitumoral imatinib with the use of ABCG2 and Pglycoprotein inhibitors, such as elacridar, the benzimidazole pantoprazole, or isoflavones (2,11,14,21,25). However, it has to be noted that the use of TCBZ for this purpose may be controversial in animals whose products are destined for human consumption or in areas of parasite endemicity due to the potential development of resistance.…”