BILIARY-SECRETION AND ENTEROHEPATIC RECYCLING OF FENBENDAZOLE METABOLITES IN SHEEP

Fenbendazole (FBZ) was administered intraruminally at 5.0 mg/kg, conta ining a trace of [C-14]-FBZ, to sheep fitted with a permanent bile duc t cannula and the behaviour of FBZ and its metabolites examined in bil e and plasma. Of the administered radiolabelled dose, 47% was secreted in bile of which 34% was accounted for as conjugated and 4% as unconj ugated (free) metabolites. Hydroxylated oxfendazole (OH.OFZ) was the m ajor biliary metabolite contributing 66%, and hydroxy-FBZ (OH.FBZ) 27% , of the total metabolites characterized. Small amounts of OFZ and hyd roxy FBZ sulphone (OH. FBZ.SO2) were also present in bile. The rapid a ppearance of OH.OFZ in bile, even before maximum concentrations of OFZ occurred in plasma, indicated that sulphoxidation and hydroxylation w as the major route of FBZ metabolism. Following intraduodenal infusion of free biliary metabolites, FBZ and its metabolites rapidly appeared in bile indicating absorption from the small intestine. When conjugat ed metabolites were infused they continued to appear in bile for a fur ther 15-20 h after cessation of infusion indicating that absorption of hydroxylated metabolites occurred largely after bacterial deconjugati on in the large intestine. Approximately 40% of biliary metabolites we re estimated to undergo enterohepatic reabsorption but they contribute d minimally to the metabolite content in plasma. It is suggested that during the process of recycling, biliary metabolites make substantial contact with parasites in the mucosa of the small and large intestine thereby contributing to the anthelmintic activity of FBZ.