Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in danofloxacin secretion into milk. In addition, the role of potential drug-drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1(-/-) mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of danofloxacin. However, the milk concentration and milk-to-plasma ratio of danofloxacin were almost twofold higher in wild-type compared with Bcrp1(-/-) mice. The in vivo interaction with ivermectin was studied in sheep after co-administration of danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of danofloxacin but significantly decreased danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug-drug interactions mediated by BCRP.
trans-Resveratrol undergoes extensive metabolism in the intestinal cells, which leads to the formation of glucuronide and sulfate conjugates. Given the important role of the breast cancer resistance protein (ABCG2/BCRP) in the efflux of conjugated forms, the present study investigates the bioavailability and tissue distribution of trans-resveratrol and its metabolites after the oral administration of 60 mg/kg in Bcrp1(-/-) mice. trans-Resveratrol and its metabolites were measured in intestinal content, plasma and tissues by HPLC. At 30 min after administration, intestinal content showed decreases of 71% and 97% of resveratrol glucuronide and sulfate, respectively, in Bcrp1(-/-), indicating a lower efflux from the enterocytes. Furthermore, the area under plasma concentration curves (AUC) of these metabolites increased by 34% and 392%, respectively, whereas a decrease in the AUC of trans-resveratrol was found. In conclusion, Bcrp1 plays an important role in the efflux of resveratrol conjugates, contributing to their bioavailability, tissue distribution and elimination.
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