The effect of co-administration of parbendazole on the disposition of oxfendazole in sheep.

Abstract

The effect of intraruminal administration of parbendazole (PBZ) on the flow rate of bile and the pharmacokinetic behaviour of oxfendazole (OFZ) was examined in sheep. PBZ given at 18, 9 and 4.5 mg/kg resulted in a dose-related reduction in bile flow rate which was also inversely related to changing concentration of PBZ and its metabolites in plasma. Co-administration of 4.5 mg PBZ/kg with 5.0 mg [14C]-OFZ/kg resulted in increased concentrations of fenbendazole (FBZ), OFZ and fenbendazole sulphone (FBZ-SO2) in plasma, although total 14C levels remained unchanged compared with that observed when OFZ alone was administered. The presence of PBZ also reduced biliary secretion of 14C by 22% and altered the relative proportions of OFZ metabolites in bile during the 72-h experimental period. The ratio of 4'-hydroxy-OFZ (OH-OFZ) to 4'-hydroxy-FBZ (OH-FBZ) changed from 7:1 in the absence of PBZ to approximately 1:1 in the presence of PBZ. There was no change in urinary or faecal 14C excretion. The PBZ-induced effects were temporary since the pharmacokinetic behaviour of OFZ given alone two weeks before was similar to that given two weeks after PBZ co-administration. It is suggested that the presence of PBZ temporarily slowed hepatic metabolism and biliary secretion of OFZ metabolites but concomitantly increased extra-biliary transfer of OFZ and/or its metabolites from plasma into the gastrointestinal tract. Elevated exposure of parasites in the gut wall to plasma-derived drug, coupled with higher concentrations of anthelmintically active OH-FBZ secreted in bile, could contribute to the previously reported increased efficacy of OFZ when co-administered with PBZ.