The ABCG2 protein in vitro transports the xenobiotic thiabendazole and increases the appearance of its residues in milk.

Thiabendazole (TBZ) is a broad-spectrum anthelmintic and fungicide used in humans, animals, and agricultural commodities. TBZ residues are present in crops and animal products, including milk, posing a risk to food safety and public health. ABCG2 is a membrane transporter which affects bioavailability and milk secretion of xenobiotics. Therefore, the aim of this work was to characterize the role of ABCG2 in the in vitro transport and secretion into milk of 5-hydroxythiabendazole (5OH-TBZ), the main TBZ metabolite. Using MDCK-II polarized cells transduced with several species variants of ABCG2, we first demonstrated that 5OH-TBZ is efficiently in vitro transported by ABCG2. Subsequently, using Abcg2 knockout mice, we demonstrated that 5OH-TBZ secretion into milk was affected by Abcg2, with a more than 2-fold higher milk concentration and milk to plasma ratio in wild-type mice compared to their Abcg2-/- counterpart.

Coadministration of ivermectin and abamectin affects milk pharmacokinetics of the antiparasitic clorsulon in Assaf sheep.

In veterinary field, drug exposure during milk production in dairy cattle is considered a major health problem which concerns dairy consumers. The induced expression of the ABC transporter G2 (ABCG2) in the mammary gland during lactation plays a significant role in the active secretion of many compounds into milk. The main objective of this study was to determine the involvement of ABCG2 in the secretion into milk of the antiparasitic clorsulon in sheep as well as the possible effect of the coadministration of model ABCG2 inhibitors such as macrocyclic lactones on this process. Cells transduced with the ovine variant of ABCG2 were used to carry out in vitro transepithelial transport assays in which we showed that clorsulon is a substrate of the ovine transporter. In addition, ivermectin and abamectin significantly inhibited clorsulon transport mediated by ovine ABCG2. In vivo interactions were studied in Assaf sheep after coadministration of clorsulon (in DMSO, 2 mg/kg, s.c.) with ivermectin (Ivomec®, 0.2 mg/kg, s.c.) or abamectin (in DMSO, 0.2 mg/kg, s.c.). After ivermectin and abamectin treatment, no relevant statistically significant differences in plasma levels of clorsulon were reported between the experimental groups since there were no differences in the area under the plasma concentration-curve (AUC) between clorsulon treatment alone and coadministration with macrocyclic lactones. With regard to milk, total amount of clorsulon, as percentage of dose excreted, did not show statistically significant differences when macrocyclic lactones were coadministered. However, the AUC for clorsulon significantly decreased (p < 0.05) after coadministration with ivermectin (15.15 ± 3.17 µg h/mL) and abamectin (15.30 ± 3.25 µg h/mL) compared to control group (20.73 ± 4.97 µg h/mL). Moreover, milk parameters such as half-life (T1/2) and mean residence time (MRT) were significantly lower (p < 0.05) after coadministration of macrocyclic lactones. This research shows that the milk pharmacokinetics of clorsulon is affected by the coadministration of ABCG2 inhibitors, reducing drug persistence in milk.

Role of the Abcg2 Transporter in Secretion into Milk of the Anthelmintic Clorsulon: Interaction with Ivermectin.

Clorsulon is a benzenesulfonamide drug that is effective in treating helminthic zoonoses such as fascioliasis. When used in combination with the macrocyclic lactone ivermectin, it provides high broad-spectrum antiparasitic efficacy. The safety and efficacy of clorsulon should be studied by considering several factors such as drug-drug interactions mediated by ATP-binding cassette (ABC) transporters due to their potential effects on the pharmacokinetics and drug secretion into milk. The aim of this work was to determine the role of ABC transporter G2 (ABCG2) in clorsulon secretion into milk and the effect of ivermectin, a known ABCG2 inhibitor, on this process. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we report that clorsulon was transported in vitro by both transporter variants and that ivermectin inhibited its transport mediated by murine Abcg2 and human ABCG2. Wild-type and Abcg2-/- lactating female mice were used to carry out in vivo assays. The milk concentration and the milk-to-plasma ratio were higher in wild-type mice than in Abcg2-/- mice after clorsulon administration, showing that clorsulon is actively secreted into milk by Abcg2. The interaction of ivermectin in this process was shown after the coadministration of clorsulon and ivermectin to wild-type and Abcg2-/- lactating female mice. Treatment with ivermectin had no effect on the plasma concentrations of clorsulon, but the milk concentrations and milk-to-plasma ratios of clorsulon decreased in comparison to those with treatment without ivermectin, only in wild-type animals. Consequently, the coadministration of clorsulon and ivermectin reduces clorsulon secretion into milk due to drug-drug interactions mediated by ABCG2.