The uptake of fenbendazole by cattle and buffalo following long-term low-level administration in urea-molasses blocks: Further studies on block formulations

Fenbendazole (Hoechst India Ltd.) was incorporated at 0.5 g/kg into urea molasses blocks made by two different processes. The proportion of the drug remaining in the blocks and the plasma concentrations of the parent compound and its metabolites were measured. Recovery of the drug in blocks made by the cold and the modified hot processes was 90% and 96%, respectively. The plasma metabolite profile revealed a plateau between days 4 and 6 of feeding in cattle and buffalo. However, the plasma concentrations of fenbendazole and its metabolites were low in buffalo compared to cattle.Abbreviations HPLC high-performance liquid chromatography - MUMB medicated urea molasses blocks - UMB urea-molasses block     

Metabolite concentrations in plasma following treatment of cattle with five anthelmintics

Plasma concentrations of anthelmintics and their metabolites were determined after cattle were treated at recommended dose rates and routes of administration. Fenbendazole, oxfendazole, febantel, albendazole and thiabendazole were given orally and oxfendazole was also administered with an intraruminal injector. After fenbendazole, oxfendazole and febantel were administered, fenbendazole, oxfendazole and fenbendazole sulphone were all detected in plasma in each case. However, there were marked differences between the three anthelmintics in the peak concentrations and areas under the plasma concentration/time curve (AUC) of these three metabolites. Intraruminal administration of oxfendazole produced higher AUC for fenbendazole and fenbendazole sulphone than did oral administration. Albendazole sulphoxide and sulphone were detected in cattle plasma after albendazole administration but no parent drug was present. These metabolites disappeared more rapidly in cattle than has been reported for sheep. Only 5(6)hydroxythiabendazole was detected in cattle plasma after thiabendazole treatment.     

Influence of subclinical nematodosis on the kinetic disposition of fenbendazole in buffaloes

The disposition kinetics of fenbendazole was studied in buffaloes subclinically infected with gastrointestinal nematodes. There was significantly reduced uptake of the drug in infected animals compared to uninfected controls. The pH of the duodenal liquor was highly alkaline compared to the acidic pH in uninfected animals. The egg count in the faeces never became zero though the numbers were reduced to a great extent compared to pre-treatment values. The influence of the host's physiology on the reduced bioavailability of fenbendazole is discussed.Abbreviations AUC area under the concentration-time curve - C _max peak concentration in plasma; - e.p.g. eggs per gram of faeces - ETH-OFZ ethyl oxfendazole - FBZ fenbendazole - FBZ-SO₂ fenbendazole sulphone - FEC faecal egg count - HPLC high-performance liquid chromatography - OFZ oxfendazole - T _1/2 half-life in plasma - T _max time to peak concentration in plasma     

Pharmacokinetics of fenbendazole following intravenous and oral administration to pigs

OBJECTIVE: To determine pharmacokinetics and metabolic patterns of fenbendazole after IV and oral administration to pigs. ANIMALS: 4 mixed-breed female pigs weighing 32 to 45 kg. PROCEDURE: Fenbendazole was administered IV at a dose of 1 mg/kg. One week later, it was administered orally at a dose of 5 mg/kg. Blood samples were collected for up to 72 hours after administration, and plasma concentrations of fenbendazole, oxfendazole, and fenbendazole sulfone were determined by use of high-pressure liquid chromatography. Plasma pharmacokinetics were determined by use of noncompartmental methods. RESULTS: Body clearance of fenbendazole after IV administration was 1.36 L/h/kg, volume of distribution at steady state was 3.35 L/kg, and mean residence time was 2.63 hours. After oral administration, peak plasma concentration of fenbendazole was 0.07 microg/ml, time to peak plasma concentration was 3.75 hours, and mean residence time was 15.15 hours. Bioavailability of fenbendazole was 27.1%. Oxfendazole was the major plasma metabolite, accounting for two-thirds of the total area under the plasma concentration versus time curve after IV and oral administration. Fenbendazole accounted for 8.4% of the total AUC after IV administration and 4.5% after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that fenbendazole was rapidly eliminated from plasma of pigs. The drug was rapidly absorbed after oral administration, but systemic bioavailability was low.     

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 g/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 g/ml respectively. Following intra-ruminal administration of oxfendazole, the peak concentrations were 0.11 and 0.18 g/ml respectively.     

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.     

A comparison of plasma metabolite levels in goats and sheep during continuous low-level administration of fenbendazole

Plasma levels of fenbendazole (FBZ) and its sulphoxide (OFZ) and sulphone (FBZ.SO₂) metabolites were measured in goats and sheep during low-level administration of FBZ given by intraruminal infusion or formulated into a urea-molasses feed supplement block (UMB). In experiment 1, 6 goats and 6 sheep were offered UMB containing 0.5 g FBZ/kg (MUMB) and individual block consumption was measured daily for 18 days. In experiment 2, some of the same animals (n=4 for each species) received FBZ by intraruminal infusion at 1, 1.5 and 3 mg/kg liveweight per day for 7 days at each dosage. FBZ, OFZ and FBZ.SO levels were determined in plasma collected every 3 days in experiment 1 and on days 4, 5 and²6 of each infusion period in experiment 2. In both experiments, higher equilibrium levels were observed for the three metabolites in sheep than in goats. Significant linear relationships were observed between the daily FBZ dosages and the plasma levels of the three metabolites in both species. The regression coefficients were significantly higher in sheep than in goats for FBZ and OFZ but not for FBZ.SO₂, and they were also significantly higher during MUMB administration than during infusion for all three metabolites in both species. FBZ is a suitable anthelmintic for incorporation into a MUMB formulation for use in livestock production systems where responses to molasses urea supplementation have been demonstrated and gastrointestinal parasitism impairs productivity. The results indicate that target dose rates for goats should be 0.75 mg/kg per day compared with 0.5 mg/kg per day for sheep.Abbreviations ANOVA analysis of variance - FBZ fenbendazole - FBZ.SO₂ fenbendazole sulphone - HPLC high-performance liquid chromatography - MUMB urea-molasses feed supplement block containing 0.5 g fenbendazole/kg - OFZ fenbendazole sulphoxide - UMB urea-molasses feed supplment block     

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.     

Disposition of fenbendazole in the goat

The disposition of fenbendazole was studied in goats after oral or IV administration. Plasma concentration vs time profiles were determined for fenbendazole and all of its metabolites. The total excretion of the drug and its metabolites in urine and feces was also measured for 6 days. A biliary cannula was inserted in 1 goat to study the excretion of fenbendazole and its metabolites into the bile. Fenbendazole was converted to its sulfoxide (oxfendazole), and the sulfone, primary amine, and p-hydroxylated metabolites. The active metabolite, oxfendazole, appeared in plasma, but only trace amounts were found in feces or urine. The major excretory metabolite was p-hydroxyfenbendazole.     

Effect of feeding urea-molasses blocks with incorporated fenbendazole on grazing dairy heifers naturally infected with gastrointestinal nematodes

Between June 1999 and August 2000, the effects of feeding medicated urea-molasses supplement blocks on the growth of dairy heifers in a marginal area of central Kenya were assessed by comparing the live-weight gain of supplemented and unsupplemented heifers grazing the same pasture. Thirty-nine heifers with an average age of 9.6 months were initially treated orally with albendazole (10 mg/kg body weight) and assigned to 3 groups: group I was fed urea-molasses blocks with incorporated fenbendazole (MUMB), group II was fed urea-molasses blocks (UMB) and group III heifers (control) received no block supplementation (NBS). Body weights of the heifers and faecal egg counts (FECs) were measured monthly and larval cultures were made of positive faecal samples of each group. The mean cumulative live-weight responses of the MUMB and UMB groups were significantly greater than the NBS group (P < 0.05). However, at the end of the experimental period, the mean weight gain of the MUMB group did not differ from that of the UMB group (P > 0.05). The FECs were moderate to low in all groups and decreased progressively with increasing age of the animals; FECs for the urea-molasses-supplemented groups remained significantly lower than those of the NBS group throughout the experimental period (P < 0.05). Haemonchus and Trichostrongylus were the predominant nematode genera found in the heifers, but Cooperia, Bunostomum and Oesophagostomum were also present. These results indicate that feeding of urea-molasses blocks substantially reduced production losses attributable to nematode infection of young grazing cattle, and confirms previous observations that well-fed animals are better able to overcome the effects of helminth infections.     

The bioavailability of febantel in dehydrated camels

In the present study the bioavailability of febantel paste and febantel suspension was investigated in the fully hydrated and the dehydrated camel. The serum concentrations of febantel and its metabolites, fenbendazole, oxfendazole and fenbendazole sulfone were determined by high performance liquid chromatography following extraction with ether. The exposure to febantel and its metabolites in fully hydrated camels was significantly higher in camels dosed with febantel paste compared to febantel suspension, as measured by AUC and C _max· The AUC and C _max of fenbendazole and oxfendazole were significantly lower in dehydrated camels as compared to control camels dosed with febantel paste. The systemic availability of febantel suspension in control and dehydrated camels was very low and differences between dehydration and control phases were insignificant. The low systemic availability of febantel in camels dosed with febantel suspension may cause nematodes to become resistant to this anthelmintic. It is, thus, suggested to increase the dose of febantel paste in dehydrated camels in order to increase the exposure to febantel and its metabolites. The binding of febantel, fenbendazole, oxfendazole and fenbendazole sulfone to camels'serum proteins was over 85%. Oxfendazole was only about 70% bound. Dehydration of 10 days did not affect the binding of these benzimidazole derivatives to serum proteins.     

Disposition of fenbendazole in the rabbit

The disposition of fenbendazole was studied in rabbits following either oral or intravenous administration. The major metabolites appearing in plasma were fenbendazole sulphoxide (oxfendazole) and fenbendazole sulphone. Calculation of the total urinary and faecal elimination of the drug and of its known metabolites showed that only 40 per cent of the dose was recovered after oral dosing; 29.7 per cent after an intravenous dose. The sulphoxide and sulphone were minor elimination products. The major excretory metabolite was p-hydroxyfenbendazole.     

Effect of feed type on the pharmacokinetic disposition of oxfendazole in sheep

The plasma concentration profiles of oxfendazole (OFZ), fenbendazole (FBZ) and FBZ sulphone (FBZ.SO2) were measured followed intraruminal administration of OFZ at 5 mg kg-1 to Merino weaners fed either dry forage or grazed on pasture lucerne clover. Plasma concentrations of OFZ and FBZ were significantly lower in sheep given the dry forage.     

Pharmacokinetics of fenbendazole in dogs

Fenbendazole was administered to dogs at a dose rate of 20 mg/kg body weight on a single occasion in gelatin capsules, on 5 consecutive days in feed, and on a single occasion as an alginate suspension. It was also administered at a dose rate of 100 mg/kg body weight on a single occasion in feed. Following single administration of 20 mg/kg fenbendazole mean maximum concentrations (Cmax) of the parent drug and its known active sulphoxide metabolite were 0.42 +/- 0.05 and 0.31 +/- 0.05 microgram/ml, respectively. Mean times until maximum concentrations were achieved (tmax) were 12.67 +/- 4.18 and 15.33 +/- 2.81 h, respectively, and areas under the plasma concentration-time curves (AUC) were 5.83 +/- 0.65 and 4.60 +/- 0.57 microgram.h/ml, respectively. Administration in feed increased the apparent bioavailability and administration for 5 consecutive days provided sustained plasma concentrations, generally greater than 0.2 microgram/ml. Administration as an alginate did not increase bioavailability or extend the persistence in plasma. It did increase the tmax to 16.80 +/- 2.93 and 20.00 +/- 2.53 h for fenbendazole and its sulphoxide metabolite, respectively. Increasing the dose from 20 mg/kg to 100 mg/kg did not substantially increase the Cmax or AUC.     

ANTHELMINTIC EFFICIENCY OF OXFENDAZOLE, FENBENDAZOLE AND LEVAMISOLE AGAINST NATURALLY ACQUIRED INFECTIONS OF OSTERTAGIA OSTERTAGI AND TRICHOSTRONGYLUS AXEI IN CATTLE

The anthelmintic efficiencies of oxfendazole, fenbendazole and levamisole, each at 4 dose rates spanning the manufacturers' recommended dosages were compared in beef cattle with naturally acquired infections of Ostertagia ostertagi and Trichostrongylus axei. In 8 of the 9 cases tested there was no significant increase in anthelmintic efficiency due to increased dose rates of any of the drugs. Percentage efficiencies and their standard errors, calculated from mean worm counts of pooled data for adult worms, developing 4th stage and early 4th stage larvae of O. ostertagi, were respectively, 86.9+/-4.2, 77.4+/-6.1, 74.5+/-7.3 for oxfendazole, 93.7+/-2.0. 80.7+/-6.8, 59.6+/-13.9 for fenbendazole and 69.7+/-6.9, 39.4+/-14.8, 31.2+/-22.6 for levamisole. Counts of O. ostertagi from cattle treated with oxfendazole and fenbendazole were not significantly different, but both were significantly lower than those from cattle given levamisole. Efficiency against T. axei exceeded 99% for all drugs. Practical implications for therapy and preventative control of ostertagiasis are discussed.     

The Influence of Supplementation with Urea–Molasses Blocks on Weight Gain and Nematode Parasitism of Dairy Calves in Central Kenya

The effect of feeding urea-molasses blocks (UMB) on the growth and gastrointestinal nematode parasitism of dairy weaner calves grazing on the same pasture was investigated on a farm in Thika District, central Kenya. Twenty-six female calves, with an average age of 9 months, were initially treated orally with albendazole (10 mg/kg body weight) and assigned into two groups: animals in group I were fed urea-molasses blocks (UMB) prepared using a cold process and those in group II were the controls. The UMB were given in the evening, when the animals returned from grazing, and were consumed during the night at a rate of 550 g/head per day. Supplementation was undertaken on three occasions for three consecutive months, between July and August 1999, and between January and March and July and September 2000. The body weights of the calves and the faecal egg counts were measured monthly and larval cultures were performed on positive faecal samples from each group. Significant differences (p < 0.05) were found in the cumulative weight gains of the two groups of calves from September onwards. The UMB group averaged (+/- SD) 311.2 +/- 14.9 g/day over the study period, while the control group averaged 235.7 +/- 23.5 g/day; the UMB group also reached breeding weight earlier (p < 0.05) than the control group. There was no significant difference (p > 0.05) in the faecal egg counts between the groups, the predominant genera of gastrointestinal nematodes in faecal cultures being Haemonchus spp. and Trichostrongylus spp. Other nematodes were Cooperia spp., Bunostomum spp. and Oesophagostomum spp.     

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.     

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

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.     

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.     

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.