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     

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     

Effects of Diet and Species on the Pharmacokinetics of Fenbendazole in Cattle

Knox, M.R. and Steel, J.W., 1997. Effects of diet and species on the pharmacokinetics of fenbendazole in cattle. Veterinary Research Communications, 21 (1), 37-43.The plasma concentration profiles of fenbendazole (FBZ), FBZ-sulphoxide (OFZ) and FBZ-sulphone were measured following intraruminal administration of FBZ at 7.5 mg/kg bodyweight in Bos taurus and B. indicus cattle offered three different diets: 100% wheaten chaff, 100% lucerne, and a 50:50 mix of these two diets. No differences between the species were apparent except for a longer time to peak plasma concentration for OFZ in the B. taurus steers fed 100% wheaten chaff. Cattle fed wheaten chaff alone gave greater areas under the concentration-time curve and longer persistence for all metabolites than when the same cattle were fed the other diets. It is concluded that the reduced rate of passage of digesta on lower-quality fibrous diets allows greater time for absorption of FBZ and its metabolites from the gut, thereby increasing systemic availability.     

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.     

In vitro ruminal biotransformation of benzimidazole sulphoxide anthelmintics: enantioselective sulphoreduction in sheep and cattle

The comparative in vitro sulphoreduction of the (+) and (-) enantiomers of albendazole sulphoxide (ABZSO) and oxfendazole (OFZ) by ruminal fluid obtained from sheep and cattle, was investigated, under anaerobic conditions, in this study. Ruminal fluid samples were obtained from Holstein steers fitted with a permanent rumen fistula and from Corriedale lambs via an oesophageal tube. Albendazole sulphoxide, incubated as either the racemic (rac) mixture or as each individual enantiomeric form, was extensively sulphoreduced to form albendazole (ABZ) by ruminal fluid from both species. The concentrations of ABZ formed at different incubation times were between 55 and 158% greater after the incubation of cattle ruminal fluid with (+) ABZSO, compared with that produced when (-) ABZSO was the incubated substrate. Similarly, the concentrations of ABZ were 1.3--3.0-fold higher when (+) ABZSO was incubated with sheep ruminal fluid. Significantly higher rates of depletion were observed for the (+) enantiomeric form when ABZSO was incubated with ruminal fluid from both species. The rates of ABZ formation from both ABZSO enantiomeric forms were significantly higher in sheep compared with cattle ruminal fluid. Fenbendazole (FBZ) was the metabolite formed after the incubation of the racemic form of OFZ with ruminal fluid obtained from both species. The metabolic profile of both OFZ enantiomers followed a similar pattern to that observed for ABZSO enantiomers. A bi-directional chiral inversion of one enantiomer into its antipode was observed. The (+) enantiomer appeared in the incubation medium when (-) ABZSO was the incubated substrate, and also the (-) antipode was detected after (+) ABZSO incubation with ruminal fluid obtained from both species. The results reported here demonstrate an enantioselective ruminal sulphoreduction of ABZSO and OFZ (substrate enantioselectivity). These findings contribute to interpret the chiral behaviour of benzimidazole-sulphoxide anthelmintics.     

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     

Comparative kinetic disposition of oxfendazole in sheep and goats before and during infection with Haemonchus contortus and Trich ostrongylus colubriformis

The kinetic disposition of [¹⁴C]-oxfendaEole (OFZ) and its metabolites, fenben-dazole (FBZ) and fenbendazole sulphone (FBZ.SO₂), in plasma and abomasal fluid were determined in Merino sheep and Angora goats before and during infection with Trichostrongylus colubriformis and Haemonchus contortus. The systemic availability (area under the plasma curve, AUC) of OFZ was significantly lower in goats (13.5 μg.h/ml) than in sheep (22.2 μg.h/ml) and was reduced with infection in goats (5.6 μg.h/ml) and sheep (15.1 μg.h/ml). The elimination of plasma [^l4C] was faster in goats than in sheep. The responses observed for [¹⁴C] were a reflection of the behaviour of OFZ. The concentration of OFZ and metabolites in abomasal fluid were similar in both species in the absence or presence of infection. However, as the mean flow rate of abomasal fluid was slower in goats (240 ml/h) than in sheep (488 ml/h), only 7% of the dose passed the pylorus in abomasal fluid of goats compared with 14% in sheep. The presence of gastrointestinal nematodes generally increased abomasal fluid flow rate but neither species nor infection had any effect on the rate or extent of [¹⁴C] excretion in urine or faeces. It is suggested that goats possess a faster hepatic metabolism than sheep resulting in more rapid elimination of OFZ.     

The use of cultured hepatocytes from goats and cattle to investigate xenobiotic oxidative metabolism

The oxidative metabolism of aldicarb (ALD), a carbamate pesticide, and fenbendazole (FBZ), an anthelmintic, was studied using cultured hepatocytes obtained from 4 goats and a bullock and incubated with ALD (50 mol/L) and FBZ (10 mol/L). The parent compounds and the metabolites were measured by HPLC. Both compounds are metabolized at the sulphur atom via two sequential oxidations, first to the sulphoxide (aldicarb sulphoxide and oxfendazole, respectively) and then to the sulphone. Oxfendazole and fenbendazole sulphone from FBZ, and aldicarb sulphoxide from ALD were found in both species. Aldicarb sulphone was not produced by the hepatocyte preparations from the bullock. The good correlation obtained comparing the in vitro results of FBZ metabolism with published in vivo dat obtained on FBZ kinetics in the same species confirmed the usefulness of in vitro models for predictive analysis of in vivo xenobiotic biotransformations.Abbreviations ALD aldicarb - ALDSON aldicarb sulphone - ALDSOX aldicarb sulphoxide - BSA bovine serum albumin - ID internal diameter - EGTA ethylene glycol bis(-aminoethyl ether) N,N,N,N-tetraacetic acid - FBZ fenbendazole - FBZSON fenbendazole sulphone - HBSS Hanks' balanced saline solution - HPLC high-pressure liquid chromatography - LDH lactate dehydrogenase - MFO mixed function oxidase - NCS newborn calf serum - OXF oxfendazole - WME Williams' Medium E     

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.     

Fenbendazole and thiabendazole in cattle: partition of gastrointestinal absorption and pharmacokinetic behaviour

Fenbendazole (FBZ) and thiabendazole (TBZ) were administered intraruminally with a single dose of an indigestible marker, chromium ethylenediaminetetra-acetate (Cr-EDTA), to cattle fitted with gastrointestinal cannulae. The amounts of anthelmintic leaving the rumen, abomasum and terminal ileum in digest a were derived by compartmental analysis of Cr-EDTA concentrations and integration of benzimidazole concentrations.
TBZ was absorbed much more rapidly from the rumen than FBZ and only about 12% of the dose left the rumen in digesta compared with 30% of the FBZ. Approximately 10% and 8% of the TBZ dose appeared at the pylorus and terminal ileum, respectively. Of the above amounts, 9% in the abomasum and practically 100% in the ileum was present as 5-OH-TBZ, indicating that metabolites of absorbed TBZ were recycled to the gastrointestinal tract. Twenty-eight percent and 52% of the FBZ appeared at the pylorus and terminal ileum, respectively, indicating a substantial recycling of absorbed drug to the small intestine. It is suggested that biliary secretion of both TBZ and FBZ and their metabolites may contribute to this recycling.
Maximal concentrations of TBZ occurred in plasma in 4 h compared with about 24 h for FBZ. TBZ and metabolites were excreted in urine much more rapidly than were FBZ and metabolites. In plasma and in each of the gastrointestinal compartments, FBZ persisted much longer than did TBZ. It was concluded that slower absorption and excretion and more extensive recycling to the gastrointestinal tract of FBZ, than of TBZ, contribute markedly to its greater potency against helminths.     

Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co-administered with piperonyl butoxide in sheep

Co-administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)-resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co-administration of PB and OFZ in sheep. Six 6-8-month-old, parasite-free, female Dorset sheep (30-40 kg) were used in a two-phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO(2)) were recovered in plasma up to 48 h post-treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co-administration of PB, were characterized by a significantly greater area under the concentration--time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO(2) following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed T(max) and a significantly delayed (> 45%) elimination (t(1/2)(el)). Although AUC values for FBZSO(2) were not significantly different between groups, this metabolite was depleted more slowly from plasma (t(1/2)(el) > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co-administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of anti-parasite therapy against BZD-resistant parasite strains.     

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.     

Assessment of the pharmacological interactions between the nematodicidal fenbendazole and the flukicidal triclabendazole: In vitro studies with bovine liver microsomes and slices

Parasitic diseases have a significant impact on livestock production. Nematodicidal drugs, such as fenbendazole (FBZ) or its oxidized metabolite oxfendazole (OFZ), can be used along with the trematodicidal triclabendazole (TCBZ), to broaden the spectrum of anthelmintic activity. However, co‐exposure to these compounds could lead to drug–drug (D‐D) interactions and eventually alter the clinical profile of each active principle. The aim of this study was to assess the presence of such interactions by means of two in vitro models, namely bovine liver microsomal fractions and bovine precision‐cut liver slices (PCLSs). To this end, an in vitro assessment involving incubation of FBZ and TCBZ or a combination of FBZ and TCBZ was carried out. Results with microsomal fractions showed a 78.4% reduction (p = .002) in the rate of OFZ production upon co‐incubation, whereas the sulfoxide metabolite of TCBZ (TCBZSO) exhibited a decreasing tendency. With PCLS, OFZ accumulation in the incubation medium increased 1.8‐fold upon co‐incubation, whereas TCBZSO accumulation decreased by 28%. The accumulation of FBZ and OFZ in the liver tissue increased upon 2‐hr co‐incubation, from 2.1 ± 1.5 to 18.2 ± 6.1 (p = .0009) and from 0.4 ± 0.1 to 1.3 ± 0.3 nmol (p = .0005), respectively. These results confirm the presence of D‐D interactions between FBZ and TCBZ. Further studies are needed to determine the extent of involvement of drug‐metabolizing enzymes and membrane transporters in interactions between compounds largely used in livestock production systems.     

Effects of anthelmintic treatment and feed supplementation on grazing Tuli weaner steers naturally infected with gastrointestinal nematodes

A study was carried out to determine the epidemiology of gastrointestinal nematodes in indigenous Tuli cattle and the effect of dietary protein supplementation and anthelmintic treatment on productivity in young growing cattle. Forty steers with an average age of 18 months were divided into 4 groups; 1) fenbendazole (slow release bolus) and cottonseed meal (FCSM group), 2) fenbendazole (FBZ group), 3) cottonseed meal (CSM group) and 4) control (no cottonseed meal and no fenbendazole) (control group). Performance parameters measured included worm eggs per gram of faeces (EPG), packed cell volume (PCV), albumin and live-weight gain. Results showed that faecal worm egg counts were lower and PCV was higher in the FCSM and FBZ groups than in the CSM and control groups (P < 0.01). Weight gains were higher in the CSM and FCSM groups than in the FBZ and control groups (P < 0.05). The cost benefits of anthelmintic treatment and dietary supplementation were apparent in this study. The improved growth performance of the FCSM, FBZ and CSM groups reflected a financial gain over the controls on termination of the study. The dominant genera of gastrointestinal nematodes on faecal culture, pasture larval counts and necropsy were Cooperia and Haemonchus. The incidences of Trichostrongylus, Oesophagostomum and Bunostomum were low.     

Prolonged administration: A new concept for increasing the spectrum and effectiveness of anthelmintics

Cambendazole (CBZ), fenbendazole (FBZ), oxfendazole (OFZ) and thiabendazole (TBZ) all inhibited the fumarate stimulated oxidation of NADH in Haemonchus contortus mitochondria. These observations plus the phenomenon of cross resistance to benzimidazoles suggested that the different benzimidazole anthelmintics affect parasitic helminths in a similar manner.The variation in efficiency and spectrum of activity may therefore be due to differences in their pharmacokinetic behaviour. To test this hypothesis, the magnitude and duration of concentrations of TBZ, FBZ and OFZ in plasma and other body compartments after administration were compared with their effectiveness against parasites. The effects of similar doses against benzimidazole-resistant. Trichostrongylus colubriformis and H. contortus were found to correlate with the period high plasma concentrations were maintained.Further evidence of this relationship was obtained by infusion or multiple drenching of TBZ to cattle harbouring arrested Ostertagia ostertagi larvae, so as to maintain high circulating concentrations for an extended period. This resulted in the removal of 90% of the arrested larvae, whereas TBZ as normally administered is considered quite ineffective against these larvae.These observations suggest that the spectrum and effectiveness of benzimidazoles may be improved by extending the period during which parasites are exposed to toxic concentrations.     

The effects of benzimidazole resistance and route of administration on the uptake of fenbendazole and thiabendazole by Haemonchus contortus and Trichostrongylus colubriformis in sheep

Radiolabelled fenbendazole (FBZ) and thiabendazole (TBZ) were administered into the rumen or abomassum of sheep previously infected with benzimidazole-susceptible or resistant Haemonchus contortus and Trichostrongylus colubriformis. Plasma radioactivity was determined for 12 hours following anthelmintic administration and at the end of this time the incorporation of radiolabel into the parasites was determined.Incorporation of radiolabel from FBZ was significantly greater in susceptible than in resistant worms. However, with TBZ there was no significant difference. There were no significant differences in the incorporation between H. contortus and T. colubriformis. Incorporation of TBZ was greater than FBZ in the worms except after ruminal administration to sheep showing clinical parasitism resulting from infection with benzimidazole- susceptible worms. TBZ was administered at five times the dose rate as FBZ, and thus a lower proportion of the administered TBZ than FBZ was incorporated.With the exception of incorporation of TBZ by resistant worms, the route of administration had a major effect on incorporation by the parasites and on plasma levels. Based on plasma levels, TBZ appeared to be rapidly absorbed from both the rumen and abomasum, whereas FBZ was less readily absorbed from the rumen with the rate of absorption being markedly greater if FBZ was administered directly into the abomasum. The findings suggest that the rumen may act as a reservoir of FBZ prolonging the period of high anthelmintic concentration in the host. This may contribute to the high efficacy of this anthelmintic.     

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.     

FASTING-INDUCED CHANGES TO THE PHARMACOKINETIC BEHAVIOUR OF ALBENDAZOLE AND ITS METABOLITES IN CALVES

The influence of fasting on the bioavailability and disposition kinetics of albendazole (ABZ) and its metabolites in cattle was investigated. ABZ (10 mg/kg) was given by intraruminal (i.r.) (Experiment 1) and intravenous (i.v.) (Experiment 2) administration to Holstein calves either fed ad libitum (control) or subjected to a 48 h fasting period (fasted group) prior to treatment. The rate of passage of digesta through the gastrointestinal (GI) tract was evaluated by measurement of cobalt faecal excretion following the oral administration of the sodium-cobalt-ethylendiamine-tetracetic acid complex to calves subjected to the feeding conditions above described. Jugular blood and abomasal fluid (via cannula) samples were collected over 120 h post-treatment; samples were analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO₂). Fasting the animals prior to the i.r. treatment resulted in pronounced modifications to the plasma and abomasal fluid disposition kinetics of ABZ and its metabolites. A greater extent of GI absorption with significantly higher C_max (150%) and AUC (310%) values for ABZSO in plasma, was observed in fasted compared to fed animals following the i.r. administration of ABZ. Extended detection of ABZ metabolites resulting in significantly longer plasma t_½el and MRT was also obtained in fasted compared to fed calves. These results correlated with the substantially enhanced availability of ABZ and its metabolites (AUCs over 200% greater) in the abomasal fluid of the fasted animals. Fasting did not induce changes to the plasma disposition of either ABZ or its metabolites after the i.v. treatment. The digesta passage rate, measured by the amount of cobalt excreted in faeces, was significantly lower in fasted compared to animals fed ad libitum. A delayed GI transit time that decreases the rate of passage of the drug down the digestive tract, may have accounted for enhanced ABZ dissolution and absorption in fasted compared to fed calves. The findings reported in this article show that fasting prior to treatment notably affects the bioavailability and disposition kinetics of ABZ and its metabolites in cattle.     

Total CK and CK‐BB activity in serum from sheep with Scrapie

Summary

Plasma metabolite levels were measured in buffalo and cross‐bred cattle after daily intraruminal administration of fenbendazole at 0.5 mg/kg body weight. An equilibrium between the absorption of fenbendazole and disposition of its metabolites could be observed between days 3 to 6 and remained almost unchanged thereafter. The buffaloes had a lower uptake of the anthelmintic and lower plasma levels of its metabolites than in cattle. The findings were compared with those obtained after a single intraruminal therapeutic dose of fenbendazole.     

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.