Enniatin B1 is a substrate of intestinal P-glycoprotein, multidrug resistance-associated protein 2 and breast cancer resistance protein

Enniatins are cyclic hexadepsipeptides produced by various fungi, known to have ionophoric, antibiotic and insecticidal activity. The aim of the present study was to evaluate the intestinal absorption characteristics of enniatin B1 (ENN-B1). Using the human intestinal Caco-2 cell line, we found that the permeability of ENN-B1 in the basolateral to apical direction was 6.7× higher as compared to the permeability in the opposite direction, indicating involvement of apically located transporters. Transport of ENN-B1 in the apical to basolateral direction was increased significantly upon treatment of Caco-2 cells with the P-glycoprotein (Pgp) inhibitor verapamil and the multidrug resistance-associated protein 2 (MRP2) inhibitor MK571, but only weakly and not significantly after treatment with the breast cancer resistance protein (BCRP) inhibitor fumitremorgin C. Additionally, MDCK II cells over-expressing Pgp, MRP2 or BCRP, showed reduced sensitivity towards ENN-B1. These data demonstrate for the first time that ENN-B1 is a substrate of MRP2 and suggests that Pgp, MRP2 and possibly BCRP are involved in transport of ENN-B1 across the intestine.