Plasma Disposition, Faecal Excretion, Metabolism and Chirality of Anthelmintic Drugs in Horses

The plasma disposition and faecal excretion of oxfendazole (FBZ.SO), fenbendazole (FBZ) and oxibendazole (OBZ), and enantiospecific disposition of FBZ.SO were investigated in horses following oral administration at a dose rate of 10 mg/kg. Fenbendazole and FBZ.SO were metabolised extensively to the sulphone metabolite. Significantly greater plasma concentrations were found for sulphone (SO2) metabolites than for the parent molecules of FBZ and FBZ.SO. The sulphone metabolite is known to have relatively very low or no anthelmintic activity. Significantly higher mean maximum concentration (Cmax) and larger area under the concentration time curve (AUC) of parent molecules were obtained for FBZ.SO (Cmax: 0.35+/-0.07 mug/ml, AUC: 4.40+/-0.90 fig.h/ml) compared to FBZ (Cmax- 0.04+/-0.01mug/ml, AUC: 0.61+/-0.01 mug.h/ml). At the same oral dose rate, it is possible that FBZ.SO produces greater activity in the systemic circulation than FBZ since the plasma concentration of active metabolite of FBZ.SO was larger than that of FBZ however the tubulin binding of FBZ.SO is much lower than FBZ and activity probably reflects both concentration present and inherent affinity for the known receptor conforming activity. High concentrations of FBZ in the gut following FBZ administration could confer good activity on the parent compound for gastrointestinal parasites. The estimated plasma concentrations of OBZ from samples were very low (Cmax- 0.006 fig/ml). In faeces the highest faecal excretion was determined at 24 h for all molecules. A high FBZ concentration (~20% of parent molecule) was found in the faecal samples after FBZ.SO administration although faecal concentrations of administered moiety were always higher. Enantiospecific analysis of FBZ.SO showed that the first enantiomer (FBZ.SO-1) was predominant in six of the eight animals whereas in two animals the second enantiomer dominated in the plasma samples. The effect of piperonyl butoxide, a cytochrome P450 inhibitor was determined on the pharmacokinetic and chiral disposition of FBZ.SO in ponies. Oxfendazole was given intravenously at a dose rate of 10 mg/kg bodyweight and piperonyl butoxide was administered by nasogastric intubation at a dose rate of 31 mg/kg bodyweight, 30 minutes prior to FBZ.SO administration. The plasma concentrations of FBZ.SO and its sulphide and sulphone metabolites were determined following administration of FBZ.SO alone or with PB. It was shown that piperonyl butoxide significantly inhibited the metabolism of FBZ.SO and increased its plasma concentration. It was apparent that one of the FBZ.SO enantiomers (FBZ.SO-2) was metabolised much more rapidly than the other enantiomer (FBZ.SO-1). On the other hand, the plasma concentrations of FBZ.SO-2 were higher than those of FBZ.SO-1 when the animals were given FBZ.SO with piperonyl butoxide. Thus the metabolism or excretion of FBZ.SO-2 was inhibited by piperonyl butoxide more effectively than that of FBZ.SO-1. Hepatic microsome samples were prepared from horse liver tissue to determine the in vitro metabolism of FBZ.SO, FBZ and OBZ with and without piperonyl butoxide. Only the sulphone metabolite was formed after FBZ.SO incubation and the sulphone, sulphoxide and hydroxy metabolite were formed after FBZ incubation. The sulphonation pathway of the metabolism of FBZ.SO and FBZ was inhibited significantly by piperonyl butoxide. The extent of metabolism for FBZ.SO and FBZ was significantly higher when the anthelmintics were incubated alone than in the presence of piperonyl butoxide. The enantiospecific metabolism was also determined following incubation of FBZ.SO as a racemate substrate and following incubation of FBZ as a prochiral drug with and without piperonyl butoxide. Microsomal metabolism was apparently enantiospecific since the enantiomers were metabolised differently from each other. There was a marked change in the enantiomer ratio when FBZ.SO was incubated with piperonyl butoxide. Fenbendazole (FBZ) metabolism to sulphoxide (FBZ.SO) was also shown to be enantiospecific since FBZ.SO-1 predominated in the reaction mixture. Piperonyl butoxide affected the enantiospecific character of the metabolism. Oxibendazole (OBZ) was metabolised extensively to its unidentified metabolites (Ml, M2, M3 and M4) and piperonyl butoxide significantly inhibited the metabolism of OBZ. Three unidentified metabolites (Ml, M2 and M4) were significantly decreased and one unidentified metabolite (M3) was significantly increased when OBZ was incubated with piperonyl butoxide. The pharmacokinctic disposition and faecal excretion of IVM, MXD and DRM were reported in horses following oral administration at a dose rate of 0.2 mg/kg. Large interindividual variations of kinetic parameters were observed from animals in this study. A similar pattern of absorption and time till Cmax (tmax) were found