Modulation of monepantel secretion into milk by soy isoflavones

Abstract

Monepantel (MNP), a novel anthelmintic drug from amino‐acetonitrile derivatives, is a substrate for breast cancer resistance protein (BCRP). BCRP‐mediated milk secretion of drugs can be altered by isoflavones. In this study, we aimed to show how soy isoflavones and BCRP inhibitors genistein (GEN) and daidzein (DAI) can modulate the secretion of MNP into milk. Moreover, we observed that the expression of BCRP in the lactating mammary gland of sheep was significantly higher than in non‐lactating sheep using Western blot analysis. These properties of MNP and MNPSO2 (monepantel sulfone, the major active metabolite of MNP), identified as a BCRP substrate in determining the interaction with BCRP, were examined by vesicular transport (VT) inhibition assays. In pharmacokinetic studies, we demonstrated the transport of MNP into milk in three experimental groups: G1 fed standard forage; G2 fed soy‐enriched forage; G3 fed standard forage paired with orally administered exogenous GEN and DAI. The concentrations of MNP and MNPSO2 were analyzed by high‐performance liquid chromatography. Compared to the control group (3.27 ± 1.13 vs. 5.46 ± 2.23), the AUC (0–840 h) milk/plasma ratio decreased by 40% in the soy‐enriched diet group. The concentrations of GEN and DAI were determined using liquid chromatography coupled with tandem mass spectrometry in soy. A VT inhibition assay was conducted to determine the IC50 values for MNP and MNPSO2 as BCRP inhibitors. This study showed that milk excretion of a BCRP substrate, such as monepantel, can be diminished by the presence of isoflavones in the diet.

ABCG2 Transports the Flukicide Nitroxynil and Affects Its Biodistribution and Secretion into Milk

“…However, further studies to confirm this hypothesis should be carried out. Furthermore, differences in ABCG2 activity due to inhibition by diet compounds such as flavonoids [ 41 , 42 ] or drugs or genetic ABCG2 polymorphism [ 3 , 43 ], not only in the mother but also in the infant, could vary the effective exposure in newborn and adults, considering also age-related changes in ABCG2 abundance [ 44 ].…”