The emerging mycotoxin, enniatin B1, down-modulates the gastrointestinal toxicity of T-2 toxin in vitro on intestinal epithelial cells and ex vivo on intestinal explants.

Enniatins, the most prevalent emerging mycotoxins, represent an emerging food safety issue, because of their common co-occurrence with other fusariotoxins such as trichothecenes co-produced by Fusarium spp on field grains and because of their extensive prevalence in grains. In this study, the intestinal toxicity of enniatin B1 (ENN) alone and mixed with the most toxic trichothecene T-2 toxin (T2) was characterized by using two biological models from pig, the most sensitive species: the intestinal cell line IPEC1 (in vitro exposure) and jejunal explants (ex vivo exposure). Dose-dependent decreases in cell proliferation in IPEC1 and in the histopathological scores of explants were observed for ENN at µM-levels and for T2 at nM-levels, with IC50 values for ENN of 15.8 and 29.7 µM, and for T2 of 9.3 and 15.1 nM in vitro and ex vivo, respectively. Interaction analysis by probabilistic and by determinist approaches showed a less than additive effect both in vitro and ex vivo, at IC50 values, with increasing antagonism with decreasing concentrations of toxins. The results obtained by the determinist median-effect dose analysis and by the nonlinear regression analysis were concordant. All the median-effect doses estimated for IPEC cells were included in the IC50 confidence intervals of the nonlinear regression fitting. Given the occurrence of enniatins, potential synergy following the co-occurrence of enniatins and the major fusariotoxins, especially trichothecene B deoxynivalenol should be investigated.

Role of P-glycoprotein in the disposition of macrocyclic lactones: A comparison between ivermectin, eprinomectin, and moxidectin in mice.

Macrocyclic lactones (MLs) are lipophilic anthelmintics and substrates for P-glycoprotein (P-gp), an ATP-binding cassette transporter involved in drug efflux out of both host and parasites. To evaluate the contribution of P-gp to the in vivo kinetic disposition of MLs, the plasma kinetics, brain concentration, and intestinal excretion of three structurally different MLs (ivermectin, eprinomectin, and moxidectin) were compared in wild-type and P-gp-deficient [mdr1ab(-/-)] mice. Each drug (0.2 mg/kg) was administered orally, intravenously, or subcutaneously to the mice. Plasma, brain, and intestinal tissue concentrations were measured by high-performance liquid chromatography. The intestinal excretion rate after intravenous administration was determined at different levels of the small intestine by using an in situ intestinal perfusion model. P-gp deficiency led to a significant increase in the area under the plasma concentration-time curve (AUC) of ivermectin (1.5-fold) and eprinomectin (3.3-fold), whereas the moxidectin AUC was unchanged. Ivermectin and to a greater extent eprinomectin were both excreted by the intestine via a P-gp-dependent pathway, whereas moxidectin excretion was weaker and mostly P-gp-independent. The three drugs accumulated in the brains of the mdr1ab(-/-) mice, but eprinomectin concentrations were significantly lower. We concluded that eprinomectin disposition in mice is controlled mainly by P-gp efflux, more so than that of ivermectin, whereas moxidectin disposition appears to be mostly P-gp-independent. Given that eprinomectin and ivermectin have higher affinity for P-gp than moxidectin, these findings demonstrated that the relative affinity of MLs for P-gp could be predictive of the in vivo kinetic behavior of these drugs.