title: 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.
authors.affiliation: CSIRO Division of Animal Health, McMaster Laboratory, Glebe, NSW, Australia.
authors.forename: D R
authors.initials: DR
authors.lastname: Hennessy
authors.forename: J W
authors.initials: JW
authors.lastname: Steel
authors.forename: R K
authors.initials: RK
authors.lastname: Prichard
authors.forename: E
authors.initials: E
authors.lastname: Lacey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D001646:Bile / Q000187:drug effects*; D004347:Drug Interactions; D005243:Feces / Q000737:chemistry; D005273:Fenbendazole / Q000097:blood; D008297:Male; D012044:Regression Analysis; D012756:Sheep / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D005273:Fenbendazole; C100292:parbendazole; C011030:oxfendazole