Pharmacokinetics of albendazole administered by an intraruminal pulse release electronic device in cattle

Albendazole was administered to 12 young Charolais cattle, 300 kg bodyweight, using an intraruminal pulse release electronic device. The device released 2 g albendazole three times at 31 day intervals. The kinetic study of two main metabolites of albendazole in all animals at the time of each release showed that on 36 occasions the devices worked at the expected time; the mean kinetic profiles were nearly identical at first, second and third release. A good repeatability was generally also noticed for each animal individually; the bioavailability of the drug did not seem to be different from that obtained after administration of albendazole as an oral drench.     

Effect of an albendazole controlled release capsule on immunity to internal parasites in sheep

Extract

During a study into internal parasitism in two lines of adult rams (aged 16 months), it was discovered that treatment with an albendazole controlled release capsule (Nufarm) in an earlier trial had affected some parameters measured in the current trial. In the earlier trial, grazing lambs (aged 6 months) received an albendazole controlled release capsule (CRC) to prevent establishment of adult parasites, or were allowed to become subclinically infected. Full results from both trials are in preparation.     

Control of gastro-intestinal parasitism in sheep with ivermectin delivered via an intraruminal controlled-release capsule

The efficacy of ivermectin delivered by an intraruminal controlled-release capsule against gastro-intestinal nematodes of sheep was evaluated under controlled conditions. In seven Australian studies involving 170 Merino or Merino x Border Leicester sheep, intraruminal capsules developed for 20-40 kg or 40-80 kg sheep, and delivering 0.8 or 1.6 mg of ivermectin/day respectively for 100 days (minimum dose 20 microg/kg/day), were evaluated. Studies were designed to test the therapeutic efficacy against naturally acquired and induced infections treated at the adult and fourth larval stage, and the prophylactic efficacy against naturally acquired and induced infections with third stage infective larvae. The predominant pathogenic nematodes of sheep were represented. Two studies included known benzimidazole- and levamisole-resistant nematode strains. Sheep were necropsied for total nematode counts 21-8.5 days after treatment. The efficacy of the ivermectin controlled-release capsule was generally >99% against all nematode species tested, including those confirmed to be benzimidazole- and levamisole-resistant. High therapeutic activity was demonstrated against existing adult and fourth larval stage nematode infections at the time of treatment, and high prophylactic efficacy was shown against incoming third stage larvae of all species and strains tested.     

Pharmacokinetics of ivermectin in sheep following intravenous, intra-abomasal or intraruminal administration

The pharmacokinetics of ivermectin in plasma following intravenous, intra-abomasal, and intraruminal administration to sheep was determined. When given intravenously, ivermectin was very slowly eliminated with a terminal half-life of 178 h and a volume of distribution at steady state of 5.3 l/kg indicating sequestration in a temporary depot. Intra-abomasal administration resulted in rapid absorption, a peak plasma concentration of 60.6 ng/ml at 4.4 h, and 100% bioavailability. However, intraruminal administration produced a much lower peak concentration (17.6 ng/ml at 23.5 h) and bioavailability (25.1%). A subsequent in vitro study indicated that ivermectin may be rapidly metabolized in the rumen.     

Pharmacokinetics of albendazole sulfoxide enantiomers administered in racemic form and separately in rats

The pharmacokinetic behaviour of albendazole sulfoxide (ABZSO) enantiomers was studied in rats after the oral administration of 10 mg/kg of rac-ABZSO, 5 mg/kg of (-)-ABZSO or 5 mg/kg of (+)-ABZSO. The disposition profiles of ABZSO enantiomers were similar in all treatments, but the calculated area under the curve for the (-)-ABZSO was higher in all cases compared with (+)-ABZSO. The results suggest that there is no chiral inversion of ABZSO enantiomers. After the administration of rac-ABZSO, 17.2% of the total dose was recovered in urine as albendazole ABZ (0.1%), albendazole sulfone ABZSO(2) (0.3%), albendazole 2-aminosulfone (ABZ-SO(2)NH(2)) (3.1%) and ABZSO (13.7%). The ratio (+) to (-) was similar in urine (1.6) and blood (1.7).     

Pharmacokinetics and bioequivalence of parenterally administered doramectin in cattle

Plasma concentrations of doramectin in 40 cattle dosed by subcutaneous (sc) or intramuscular (i.m.) injection (200 μg/kg) were compared to assess the bioequivalence of the two routes of administration. Peak concentration ( C _max), and areas under the concentration curve ( AUC_0– ) were determined from plasma concentrations. Animals treated by the sc route showed a mean AUC_0– of 457 ± 66 ng±day/mL (± SD) and a mean C _max of 27.8 ± 7.9 ng/mL. Results from the i.m. treatment group showed a mean AUC _0– of 475 ± 82 ng-day/mL and a mean C _max of 33.1 ± 9.0 ng/mL Absorption constants ( k _a) determined by modelling were 0.542 ± 0.336 day^-1after sc administration and 0.710 ± 0.357 day^-1after i.m. administration. The 90% confidence limits on the difference between mean AUC _0– values for the sc and i.m. groups fell within 20% of the mean value for the subcutaneous group. C _max was somewhat greater for the i.m. route. The 90% confidence limits on the difference in mean In ( T _max+1) also fell within 20% of the mean sc value. Based on this analysis, bioequivalence of the sc and i.m. formulation has been established.     

Pharmacokinetics and pharmacodynamics of tilmicosin in sheep and cattle

Tilmicosin is a long-acting macrolide antibiotic currently approved for treatment of bovine respiratory disease in the USA. Serum pharmacokinetics of tilmicosin were compared between cattle (major species) and sheep (minor species) after subcutaneous injection in order to evaluate a new potential application of the drug in currently nonapproved species. There were no significant differences in the elimination rates, maximum serum concentrations, half-lives ( t _1/2), areas under the curve ( AUC ), areas under the first-moment curve ( AUMC ), and mean residence times. Volume of distribution ( V d_area) and clearance ( Cl ), when normalized by body weight, were also similar. The only significantly different parameter was time at which maximum drug concentration was reached ( t _max), with sheep having the t _max of 3.9 h, compared to 0.5 h in cattle.
  Although macrolides are considered to be one of the safest anti-infective drugs, adverse cardiovascular effects of several macrolides have been reported. The cardiopulmonary effects of tilmicosin were monitored in healthy adult sheep after receiving a single subcutaneous (s.c.) injection of tilmicosin at the dose of 10 mg/kg, and no significant changes were found. The study indicates that tilmicosin can be used safely and effectively in sheep at the given dose, with no adverse cardiopulmonary effects.     

Pharmacokinetics of carprofen administered intravenously to sheep.

Carprofen was administered intravenously to sheep at two dose rates (0.7 and 4.0 mg kg-1), and the pharmacokinetics of the drug studied. Plasma concentrations of the drug were measured by high performance liquid chromatography. Carprofen had a small volume of distribution (Vd[area], 95.5 and 118.4 ml kg-1), a prolonged elimination half-life (t1/2 beta, 26.1 and 33.7 hours) and a slow body clearance rate (Clb, 2.5 ml kg-1 h-1) in sheep.     

Effect of a controlled-release albendazole capsule on parasitism and productivity of sheep

The efficacy of intraruminal albendazole (ABZ) capsules (Proftril-Captec®) and the effect of treatment on productivity were studied in 300 ewes infected with gastrointestinal nematodes and the trematode Dicrocoelium dendritimcum, Coprological tests revealed that treated animals remained negative for 10 weeks after the administration of capsules. Contamination of pasture with nematode larvae was significantly reduced during the whole experiment. Necropsy of 14 animals (seven treated and seven untreated) showed 96.9–99.2% efficacy against the nematodes Nematodirus spp., Oesophagostomum spp., Cooperia spp., Trichostrongylus spp. and Trichuris ovis, while efficacy was 88.5% against D. dendriticum. During the 6 month pasture season (May–October 1989), treated ewes produced on average 2.56 kg cheese and 0.6 kg wool per ewe more than untreated controls. Our study confirms the reliability of the ABZ slow-release capsules over 90 days and the positive effect of treatment on nematode contamination of pasture and ewe productivity.     

The efficacy of an albendazole intraruminal controlled-release device against gastrointestinal parasitism in lambs.

The effectiveness of albendazole in a controlled-release bolus in controlling gastrointestinal nematodes in lambs was assessed during the summer of 1986. Faecal egg counts were almost entirely negative throughout in the treated group and larval challenge remained low at below 2000 larvae kg-1. Untreated control lambs showed a characteristic pattern of auto-infection, culminating in a peak pasture larval count of over 70,000 larvae kg-1 and an outbreak of parasitic gastroenteritis in September associated with a serum pepsinogen concentration of 1.183 IU tyrosine and a mean worm burden of 91,165 nematodes at necropsy, including Ostertagia, Trichostrongylus and Nematodirus species. Subject to the restrictions imposed by the size of the bolus, this was considered to be a highly effective method of seasonal parasite control.     

The efficacy of a controlled-release albendazole capsule in suppressing nematode burdens in sheep

An experiment was undertaken between July and November 1985 in East Gippsland, Victoria, to determine the efficacy of an intra-ruminal controlled-release albendazole capsule against naturally acquired worm burdens and larval challenge in Merino hoggets. Two groups of 20 sheep, one group untreated, the other dosed with a capsule were grazed together; 5 sheep from each group were slaughtered for total worm counts 30 and 101 d after capsules were administered. Serum anthelmintic concentrations, faecal egg counts and body weights were monitored. Most capsules were exhausted within 91 d of administration. During the estimated 80 d for which they remained active the capsules were highly effective against the benzimidazole-susceptible worm populations. Faecal egg counts were reduced to zero and total worm populations were reduced by over 97% 30 d after administration. By 101 d egg counts were increasing and worm counts indicated that sheep were becoming reinfected. Sheep treated with the capsules grew faster than those not treated.     

Chiral behaviour of the metabolite albendazole sulphoxide in sheep, goats and cattle

Three sheep, three goats and three cattle were dosed orally with 5.0, 7.5 and 10 mg albendazole kg-1 bodyweight, respectively. Blood samples were taken at intervals for 48 hours after administration. The enantiomeric ratio of the metabolite albendazole sulphoxide (SO.ABZ) was determined by liquid chromatography on chiral stationary phases. At To, the plasma concentration ratio (+)SO.ABZ/(-)SO.ABZ was estimated at 3.0 in sheep, 1.5 in goats and 4.0 in cattle. The proportion of the (+) enantiomer then increased linearly as a function of time during the course of the kinetics. In comparison to the area under the curve for total SO.ABZ, the (+) enantiomer represented 86 per cent in sheep, 80 per cent in goats and 91 per cent in cattle. The specific behaviour of the two enantiomers is probably the result of the enantioselectivity of the flavine adenosine dinucleotide and cytochrome P450 dependent enzymatic systems which are involved in the sulphoxidation and the sulphonation of ABZ.     

Pharmacokinetics of a long-acting chloramphenicol formulation administered by intramuscular and subcutaneous routes in cattle

The pharmacokinetic properties of a long-acting formulation of chloramphenicol were determined in six yearling cattle after a single intravenous (i.v.) administration (40 mg/kg body weight) and after two sequential subcutaneous (s.c.) or intramuscular (i.m.) administrations (90 mg/kg/48 h). The two extravascular routes were studied during a crossover trial for a bioequivalence test. After i.v. administration, the plasma concentration-time graph was characteristic of a two-compartment open model. Mean values were a half-life of 4.1 h, a volume of distribution of 0.86 l/kg and a body clearance of 0.128 l/kg/h. Plasma concentrations of chloramphenicol following i.m. and s.c. administrations increased slowly to a broad peak at 10-15 micrograms/ml between 9 and 12 h. Bioavailability was 19.1% after i.m. injection and 12.4% after s.c. administration. The extent of absorption from the two routes did not differ significantly. The rate of absorption was significantly lower after s.c. application than it was after i.m. injection. The time necessary for the plasma concentration to exceed 5 micrograms/ml was the same for the two routes. Thus, i.m. and s.c. routes are bioequivalent.     

Pharmacokinetics of selenium administered parenterally at toxic doses in sheep

Pharmacokinetics of Se were evaluated in 24 female crossbred sheep, 8 to 14 months of age, after toxic doses of Se were administered. Five groups of 4 sheep each were given 0.4, 0.6, 0.7, 0.8, or 1 mg of Se/kg of body weight, IM. Nine of these sheep died within 36 hours after Se administration. Blood Se disappearance curves were triphasic for the 11 sheep that lived for at least 36 hours after Se administration and were biphasic for the 9 sheep that died within 36 hours. The lambda 2 rate constants of Se disposition after IM administration indicated a dose dependency. Sheep given 0.4, 0.6, 0.7, or 0.8 mg of Se/kg had lambda 2 rate constants of 0.110, 0.079, 0.046, and 0.034 hour-1, respectively (r2 = 0.97). The respective half-lives of the 2nd distributive phase after IM administration were 6.3, 8.8, 15.1, and 20.4 hours. In the 11 sheep that had triphasic pharmacokinetics, the mean lambda 3 elimination rate was 0.0011 hour-1. Four additional sheep were given 0.7 mg of Se/kg, IV. These sheep survived and had blood Se disappearance curves that were triphasic. In the 4 sheep given Se IV, the mean lambda 3 elimination rate was 0.0020 hour-1, which represented a biological half-life of 354 hours or 14.7 days.     

Uptake of albendazole and albendazole sulphoxide by Haemonchus contortus and Fasciola hepatica in sheep

The pattern of in vivo uptake of albendazole (ABZ) and its major metabolite, ABZ-sulphoxide (ABZSO), by Haemonchus contortus and Fasciola hepatica recovered from ABZ-treated sheep, was investigated. Concentration profiles of both compounds were simultaneously measured in target tissues/fluids from the same infected sheep. In addition, the proportion of the (+) and (-) ABZSO enantiomers was determined in plasma, bile and F. hepatica recovered from treated sheep. Sheep naturally infected with H. contortus were intraruminally (i.r.) treated with ABZ (micronized suspension, 7. 5mg/kg) and the plasma concentrations of ABZSO and ABZ-sulphone (ABZSO(2)) determined in addition to the concentration of ABZ and ABZSO in H. contortus, abomasal mucosa and fluid content samples. In addition, F. hepatica artificially infected sheep were treated i.r. with the same ABZ suspension (7.5mg/kg), and samples of blood, bile, liver tissue and adult flukes were collected and analysed by HPLC to determine the concentrations of ABZ and both enantiomers of ABZSO. ABZSO and ABZSO(2) were the analytes recovered in plasma with ABZ and ABZSO present in H. contortus. ABZ was the analyte recovered at the highest concentration in H. contortus and abomasal mucosa, whereas higher concentrations of ABZSO were measured in abomasal fluid content. Only low concentrations of ABZ were detected in F. hepatica and bile, but markedly higher concentrations of ABZ were measured in liver tissue. ABZSO was the main molecule recovered in F. hepatica, plasma and bile samples collected from ABZ-treated sheep. The (+) enantiomer of ABZSO was recovered at a higher proportion in plasma (75%), bile (78%) and F. hepatica (74%) after ABZ administration to infected sheep.