The pharmacokinetics of fenbendazole and oxfendazole in cattle

The pharmacokinetics of fenbendazole and oxfendazole in cattle are described. The pharmacokinetics of oxfendazole were not significantly different when administered orally and by intra-ruminal injection. At a dose rate of 4.5 mg/kg, administered orally, fenbendazole gave rise to mean peak concentrations in plasma of fenbendazole and oxfendazole of 0.11 and 0.13 microgram/ml respectively. Oral administration of oxfendazole, at 4.5 mg/kg body weight, gave rise to plasma peak concentrations of fenbendazole and oxfendazole of 0.10 and 0.20 microgram/ml respectively. Following intra-ruminal administration of oxfendazole, the peak concentrations were 0.11 and 0.18 microgram/ml respectively.     

Comparative pharmacokinetics of fenbendazole in buffalo and cattle

Swamp buffalo (Bubalus bubalis) and Droughtmaster cattle (Bos indicus × B. taurus), fitted with gastrointestinal cannulae, were dosed intraruminally with fenbendazole at 7.5 mg/kg liveweight, together with a chromium oxide capsule and a pulse dose of NaCoEDTA, to estimate the flow dynamics of the digesta in the rumen and duodenum. The concentrations of fenbendazole (FBZ) metabolites were measured in plasma and duodenal fluid collected over 120 h. In plasma, significantly lower peak concentrations and earlier disappearance of FBZ and its sulphoxide (OFZ) metabolite were observed in buffalo, which considerably reduced systemic availability in comparison with cattle. The availability of OFZ in the duodenal fluid of buffalo was significantly lower, whereas FBZ disposition was similar to that in cattle. The turnover rate of fluid in the rumen was higher in buffalo than in cattle, while the flow parameters for other digesta were similar in the two species. It is concluded that the decreased absorption of drug in buffalo was attributable to the shorter residence time of the dose in the rumen, and probably in the entire gastrointestinal tract. This may reduce the efficacy of treatment and indicate the need for higher dose rates for benzimidazole anthelmintics in buffalo than in cattle.Abbreviations AAS atomic absorption spectroscopy - AUC area under the concentration-versus-time curve - C _max maximum concentration - FBZ fenbendazole - FBZ.SO₂ fenbendazole sulphone - HPLC high-performance liquid chromatography - OFZ fenbendazole sulphoxide     

Comparative plasma disposition of fenbendazole, oxfendazole and albendazole in dogs

The plasma disposition of fenbendazole (FBZ), oxfendazole (OFZ) and albendazole (ABZ); and the enantiospecific disposition of OFZ, and ABZSO produced were investigated following an oral administration (50 mg/kg) in dogs. Blood samples were collected from 1 to 120 h post-administration. The plasma samples were analysed by high performance liquid chromatography (HPLC). The plasma concentration of FBZ, OFZ, ABZ and their metabolites were significantly different from each other and depended on the drug administered. The sulphone metabolite (FBZSO2) of FBZ was not detected in any plasma samples and the parent molecule ABZ did not reach quantifiable concentrations following FBZ and ABZ administration, respectively. OFZ and its sulphone metabolite attained a significantly higher plasma concentration and remained much longer in plasma compared with FBZ and ABZ and their respective metabolites. The maximum plasma concentrations (Cmax), area under the concentration time curve (AUC) and mean residence time (MRT) of parent OFZ were more than 30, 68 and 2 times those of FBZ, respectively. The same parameters for ABZSO were also significantly greater than those of FBZSO. The ratio for total AUCs of both the parent drug and the metabolites were 1:42:7 for following FBZ, OFZ and ABZ administration, respectively. The enantiomers were never in racemic proportions and (+) enantiomers of both OFZ and ABZSO were predominant in plasma. The AUC of (+) enantiomers of OFZ and ABZSO was, respectively more than three and seven times larger than that of (-) enantiomers of both molecules. It is concluded that the plasma concentration of OFZ was substantially greater compared with FBZ and ABZ. The data on the pharmacokinetic profile of OFZ presented here may contribute to evaluate its potential as an anthelmintic drug for parasite control in dogs.     

Disposition of fenbendazole in cattle

Fenbendazole (FBZ) was administered to cattle IV and orally in a crossover design. Plasma concentration vs time profiles were reported for FBZ and its major metabolites, the sulfoxide (oxfendazole) and the sulfone. The total excretion of FBZ and its metabolites in urine and feces was also measured for 6 days after administration. All known metabolites were identified in urine and feces except for fenbendazole amine. Neither this minor metabolite nor p-hydroxyfenbendazole (FBZ-OH) appeared in plasma. The major excretory product was FBZ-OH. After oral administration, only 44.6% of the dose was eliminated after 6 days, indicating a fairly high degree of sequestration, probably within the gastrointestinal tract.     

Safety of fenbendazole use in cattle

Fenbendazole (Panacur: Hoechst) has a low degree of toxicity, teratogenicity and adverse effects on the reproductive tract, and a high degree of safety in experimental animals. Acute, subacute and long-term toxicity trials in cattle given fenbendazole at dosages of up to 2 g/kg revealed no adverse effects. Studies of teratogenicity, effects on fertility, compatibility with other drugs, and safety for animal handlers had similarly negative results.     

Pharmacokinetic behaviour of fenbendazole in buffalo and cattle

Sanyal, P.K. Pharmacokinetic behaviour of fenbendazole in buffalo and cattle. J. vet. Pharmacol. Therap. 17, 1–4.
Concentrations of fenbendazole and of drug metabolites in plasma were measured in buffalo and cross-bred cattle after single intraruminal administration at two different doses. Plasma concentrations of the parent compound fenbendazole and the two metabolites, viz. oxfendazole and fenbendazole sulfone, were much lower in buffalo compared with cattle, at a dose of 7.5 mg/kg body weight as indicated by lower area under concentration curve and concentration maximum. At a dose of 15 mg/kg body weight there were corresponding increases in plasma metabolite concentrations in cattle. However, buffaloes did not show a similar corresponding increase.     

Isolation of oxfendazole resistant Cooperia oncophora in cattle

A field strain of Cooperia oncophora resistant to oxfendazole was isolated from a commercial cattle rearing property in Waikato, New Zealand. Resistance to oxfendazole was assessed by means of a faecal egg count depression test and an in vitro egg hatch test. This is the first documented case of anthelmintic resistance in Cooperia spp. and the first report of anthelmintic resistance in cattle in New Zealand.     

Influence on the antithyroid compound methimazole on the plasma disposition of fenbendazole and oxfendazole in sheep

The influence of methimazole on the plasma disposition kinetics of fenbendazole, oxfendazole and their metabolites, was investigated in adult sheep. The two anthelmintics were administered by oral drench at 5 mg kg⁻¹ either alone (control treatments) or together with methimazole given orally at 3 mg kg⁻¹. Blood samples were taken serially for 144 hours. Fenbendazole parent drug and its sulphoxide and sulphone metabolites were the three analytes observed by high performance liquid chromatography ( ) after the administration of both anthelmintics. The disposition of each analyte followed a similar pattern after the administration of the two anthehnintics alone. Oxfendazole was the main component recovered in plasma between four and 120 to 144 hours after the administration of both anthelmintics either with or without methimazole. A modified pattern of disposition, with significantly higher C_max and values for fenbendazole parent drug, and a delayed appearance in plasma with retarded T_max values for the sulphoxide and sulphone metabolites, were the main pharmacokinetic changes observed when the drugs were administered with methimazole.     

Comparative plasma disposition kinetics of albendazole, fenbendazole, oxfendazole and their metabolites in adult sheep

The comparative plasma disposition kinetics of albendazole (ABZ), fenbendazole (FBZ) and oxfendazole (OFZ) following their oral administration (5 mg/kg) to adult sheep was characterized. Jugular blood samples were taken serially over a 144 h period and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO₂) (ABZ treatment), and for FBZ, OFZ and FBZ sulphone (FBZSO₂) (FBZ and OFZ treatments). While the ABZ parent drug was not detected at any time post-treatment, ABZSO and ABZSO₂ were the analytes recovered in plasma, after oral administration of ABZ to sheep. The active ABZSO metabolite was the main analyte recovered in plasma (between 0.25 and 60h post-treatment), accounting for 71 % of the total AUC. FBZ, OFZ and FBZSO₂ were the analytes detected in plasma following the oral administration of both FBZ and OFZ to sheep. Low concentrations of FBZ were found in plasma between 4 (FBZ treatment) or 8 h (OFZ treatment) and 72 h post-treatment. The plasma profile of each analyte followed a similar pattern after both treatments; OFZ being the main component detected in plasma. The plasma disposition of ABZ metabolites was markedly different to that of FBZ derivatives. ABZSO exhibited faster absorption and a higher C_max than OFZ (both treatments). Furthermore, while ABZSO declined relatively rapidly in plasma reaching non-detectable concentrations at 60 h post-ABZ administration, OFZ was found in plasma for up to 120 (FBZ treatment) and 144 h (OFZ treatment). The extended detection of OFZ in plasma in both treatments correlated with the prolonged t_1/2β (18 h) and mean residence time (MRT) (30–33 h) obtained for this metabolite compared to those of ABZSO (t_1/2β= (7.0 h); MRT= 12.5 h). These differences between the disposition of ABZ and FBZ metabolites may account for differences in their patterns of efficacy and tissue residues.     

Plasma disposition and faecal excretion of oxfendazole, fenbendazole and albendazole following oral administration to donkeys

Fenbendazole (FBZ), oxfendazole (fenbendazole sulphoxide, FBZSO), and albendazole (ABZ) were administered orally to donkeys at 10mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment. The plasma and faecal samples were analysed by high performance liquid chromatography (HPLC). The parent molecule and its sulphoxide and sulphone (FBZSO(2)) metabolites did not reach detectable concentrations in any plasma samples following FBZ administration. ABZ was also not detected in any plasma samples, but its sulphoxide and sulphone metabolites were detected, demonstrating that ABZ was completely metabolised by first-pass mechanisms in donkeys. Maximum plasma concentrations (C(max)) of FBZSO (0.49microg/mL) and FBZSO(2) (0.60microg/mL) were detected at (t(max)) 5.67 and 8.00h, respectively, following administration of FBZSO. The area under the curve (AUC) of the sulphone metabolite (10.33microg h/mL) was significantly higher than that of the parent drug FBZSO (5.17microg h/mL). C(max) of albendazole sulphoxide (ABZSO) (0.08g/mL) and albendazole sulphone (ABZSO(2)) (0.04microg/mL) were obtained at 5.71 and 8.00h, respectively, following ABZ administration. The AUC of the sulphoxide metabolite (0.84microg h/mL) of ABZ was significantly higher than that of the sulphone metabolite (0.50microg h/mL). The highest dry-faecal concentrations of parent molecules were detected at 32, 34 and 30h for FBZSO, FBZ and ABZ, respectively. The sulphide metabolite was significantly higher than the parent molecule after FBZSO administration. The parent molecule was predominant in the faecal samples following FBZ administration. After ABZ administration, the parent molecule was significantly metabolised, probably by gastrointestinal microflora, to its sulphoxide metabolite (ABZSO) that showed a similar excretion profile to the parent molecule in the faecal samples. The AUC of the parent FBZ was significantly higher than that of FBZSO and ABZ in faeces. It is concluded that the plasma concentration of FBZSO was significantly higher than that of FBZ and ABZ. Although ABZ is not licensed for use in Equidae, its metabolites presented a greater plasma kinetic profile than FBZ which is licensed for use in horses. A higher metabolic capacity, first-pass effects and lower absorption of benzimidazoles in donkeys decrease bioavailability and efficacy compared to ruminants.     

The uptake of fenbendazole by cattle and buffalo following long-term low-level administration in urea-molasses blocks

Fenbendazole (Panacur bolus, Hoechst India Ltd) was incorporated at a rate of 0.5 g/kg into urea-molasses blocks made by two different processes. The concentration of the drug in blocks and its bioavailability were measured using plasma oxfendazole as marker. The recovery of the drug in blocks made by a warm process was 68% and the plasma oxfendazole concentration remained fairly stable at 0.2 and 0.12 µg/ml from day 6 of feeding in cattle and buffalo, respectively. The drug seemed to be inactivated in blocks made by a hot process, with reduced bioavailability. A low and sustained plasma concentration of the active metabolite of the drug could be maintained by self-medication using urea-molasses blocks as fenbendazole carrier.Abbreviations FBZ fenbendazole - HPLC high-performance liquid chromatography - MUMB medicated urea-molasses blocks - OFZ oxfendazole - UMB urea-molasses block     

Evaluation of four forms of oxfendazole against nematodes of cattle.

Oxfendazole, methyl [5-(phenylsulfinyl)-1H-benzimidazol-2-yl] carbamate, was evaluated in calves naturally infected with endoparasites. The compound was used as a drench, a paste, a bolus, and as top-dress crumbles at a dosage of 2.5 mg/kg of body weight. The four formulations produced similar effects and were 99% to 100% effective in removing the following adult parasite genera: Haemonchus, Ostertagia, Trichostrongylus. Cooperia, Bunostomum, Oesophagostomum, and Dictyocaulus. Mean efficacy against Trichuris spp varied from 87% to 95%, depending on the formulation used.     

Efficacy of oxfendazole against inhibited Ostertagia ostertagi in naturally infected cattle.

Oxfendazole was administered to pregnant cows at 2.5 and 5 mg/kg body weight to determine the anthelmintic efficacy against naturally acquired larvae which became inhibited at the early 4th stage. The experimental design included three groups of orally-treated cows, that is, 10 placebo treated control cows, 11 cows treated with 2.5 mg/kg of oxfendazole and 10 cows treated with 5.0 mg/kg of oxfendazole. Oxfendazole at 2.5 mg/kg body weight was 82 and 94% effective against EL-4 and adult O. ostertagi, respectively. At 5 mg/kg, Oxfendazole was 95 and 99% effective against EL-4 And adult O. ostertagi, respectively. The results suggested the use of a field dosage level of 5 mg/kg body weight oxfendazole where inhibited larvae may be encountered.     

Bioavailability and pharmacokinetics of metoclopramide in cattle

The bioavailability of metoclopramide was investigated in three steers following administration of 8 mg/kg by the oral, abomasal (cannula), and intravenous routes, using a Latin square design. The mean (± SD) oral and abomasal bioavailabilitles were 51.3 ± 30.7% and 76.2 ± 15.5%, respectively. The mean value for clearance ( C1 ) was 20.1 ± 5.9 ml/min and the volume of distribution ( V _d) was 0.51 ± 0.19 1/kg. Additionalpharmacokmetic parameters for metoclopramide were determined following intravenous administration to seven cows. A predominate two-compartment model of distribution was found in six cows with a t _1/2α harmonic mean of 24.2 min and a range of 11.2–72.4 min, a t _1/2β harmonic mean of 53.1 min and a range of 31.1–134.1 min, a Cl of 42.2 ± 8.7 ml/min, and a V _d of 2.1 ± 0.8 1/kg. To better define the relationship between metoclopramide concentration and release of prolactin, a treatment-by-subjects infusion study was conducted in which four different loading doses followed by constant infusion were used. A steady-state metoclopramide concentration ( MCP _ss) of 8.8 ± 2.6 ng/ml was associated with a three-fold elevation of prolactin to a mean value of 12.1 ± 3.1 ng/ml in six yearling steers. Steady state serum prolactin concentrations ( PRL _ss) did not rise significantly above 23.3 ± 6.9 ng/ml, even when MCP _ss reached a concentration of 518.5 ±151.2 ng/ml. The short half-life, moderate V _d, low minimum pharmacologically effective concentration, and rapid C1 found for metoclopramide in cattle in this study, suggest that a continuous release device could potentially be useful in the application of this drug in the prevention and treatment of fescue toxicosis.     

The efficiency of levamisole, thiabendazole and fenbendazole against naturally acquired infections of Ostertagia ostertagi in cattle

In two experiments, conducted in cattle with naturally acquired infections of Ostertagia ostertagi, comparative assessments were made of the anthelmintic efficiency of levamisole, thiabendazole and fenbendazole, each at 1.0, 1.5 and 2.0 times the recommended dose rate. Variable efficiencies of 81 and 49 per cent for levamisole, 86 and 56 per cent for thiabendazole were obtained against adult O ostertagi. Neither drug showed substantial activity against early fourth stage larvae. Efficiency of fenbendazole against adult O ostertagi was consistently high; 85 and 89 per cent in the two experiments respectively. In the first experiment in which cattle were slaughtered two to three days after treatment, only 22 per cent of inhibited early fourth stage larvae were removed whereas in the second experiment when slaughter took place 10--11 days after treatment, this efficiency was 89 per cent. There was no increased effect of increased dose rates on treatments with thiabendazole or fenbendazole. The activity of levamisole against adult worms and inhibited larvae was increased at twice the recommended dose rate.