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.     

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.     

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.     

Chirality of the sulphoxide metabolites of fenbendazole and albendazole in sheep

Two prochiral sulphide drugs, fenbendazole (FBZ) and albendazole (ABZ) were administered orally to sheep. Blood samples were analysed for parent drug and S-oxidation metabolites and the chirality of the sulphoxide metabolites was determined. The plasma concentrations of the enantiomers of the sulphoxides were never a racemate. On the contrary, the ratios were greater than 1 as soon as the sulphoxide compounds could be detected in plasma. They subsequently increased linearly throughout the time course of the kinetics, reaching the level 86:14 after FBZ and 95:5 after ABZ treatment. The major enantiomer represented 74% and 86% of the total AUC of SO.FBZ and SO.ABZ, respectively.     

The disposition of albendazole in sheep

Albendazole (ABZ) was administered intraruminally at 4.75 mg/kg to sheep fitted with a permanent bile-duct cannula to determine if its metabolites might contribute to its flukicidal action. ABZ metabolism was consistent with first-pass clearance by the liver, resulting in ABZ sulphoxide (ABZ-SO) and ABZ sulphone (ABZ-SO2) being present in plasma at maximum concentrations (mean Cmax +/- SD) of 2.0 +/- 0.2 micrograms/ml and 0.4 +/- 0.1 micrograms/ml after 8 +/- 3 h and 24 +/- 5 h, respectively. ABZ-SO, but more particularly ABZ-SO2, appeared to bind to plasma proteins but their clearance rates from plasma were similar. Biliary ABZ metabolites were mainly unconjugated ABZ-SO and 2OH-ABZ-SO (8.0% dose) or conjugated glucuronide and sulphate esters (6.3% dose) mainly of 2OH-ABZ-SO and 2OH-ABZ-SO2. The concentration of the major biliary metabolite, unconjugated ABZ-SO, followed a similar time profile to that of ABZ-SO in plasma except that Cmax was much higher (6.2 +/- 2.2 micrograms/ml). Intraruminal administration of ABZ reduced bile flow rate by 30% which may be attributable to an inhibitory effect of ABZ on microtubule formation in hepatic secretory cells. It is suggested that ABZ is sequestered in the liver. This is unlikely to contribute to its flukicidal action, which is probably attributable to ingestion of ABZ-SO from bile and blood by the fluke.     

Gastrointestinal distribution of albendazole metabolites following netobimin administration to cattle: relationship with plasma disposition kinetics

The gastrointestinal (GI) distribution and plasma disposition kinetics of alberidazole (ABZ) metabolites after oral administration of netobirnin (NTB) to cattle were studied. Eight Holstein steers (150–180 kg) were surgically fitted with permanent cannulae in the rumen, abomasum and ileum. After post-surgical recovery, the ariinials were treated orally with a suspension of neto1)imin zwitterion (400 mg/ml) at 20 nig/kg. Jugular blood and ruminal, abomasal arid ileal fluid samples were taken serially over a 96 h period and analysed by HPLC for NTB and its metabolites, including ABZ, ABZ sulphoxide (ABZSO), AH% sulphone (ABZSO?) and amino-albendazole sulphone (NHp4BZSOy). N T B parent drug was only fonnd in the G I tract and for only 12–18 h post-treatment. ABZSO and ABZSOp were the main metabolites found in plasma, being present for 30–36 h. These metabolites were exchanged between plasma and different GI fluids and were greatly concentrated in the abomasum. This phenornenori may account for the presence of ABZ, ABZSO and ABZSO? in the GI tract f'or 72 h post-treatment despite the fact that ABZ was riot detected in plasma and ABZSO and ABZSO.;, were detected for only 30–36 h in plasma. The presence o f ABZ and ABZSO in the abomasum and intestine for this extended period of time is probably relevant for anthelmintic efficacy against GI parasites. The NH₂ ABZSO₂ metabolite was detected in plasma, abomasum and ileum and its disposition kinetics were characterized for the first time.     

The efficacy of fenbendazole and albendazole against immature and adult stages of benzimidazole-resistant sheep trichostrongylids

The efficacy of two recently introduced benzimidazole anthelmintics, albendazole and fenbendazole, was determined for six-day, 10-day and adult stages of resistant strains of Haemonchus contortus and Trichostrongylus colubriformis. Albendazole, at 3.8 mg/kg reduced H contortus worm counts by 92.4, 70.8 and 67.1 per cent while fenbendazole, at 5.0 mg/kg, reduced worm burdens by 51.7, 95.5 and 93.4 per cent against six-, 10- and 25-day-old parasites respectively. For T colubriformis, the corresponding reductions with albendazole were 97.7, 95.8 and 64.9 per cent and for fenbendazole 29.0, 66.3 and 33.4 per cent. Compared with susceptible strains of H contortus and T colubriformis, for which therapeutic doses of benzimidazole anthelmintics are generally highly active against all stages of development, the present results show that these drugs do not have a uniform level of activity against all developmental stages of resistant strains.     

A correlation of toxicity of albendazole and oxfendazole with their free metabolites and bound residues

The possible correlations between embryotoxicity, plasma kinetics of toxic metabolites and covalent binding of metabolites to foetal tissues were studied using two drugs, albendazole and oxfendazole. In the rat, the metabolic inhibitor, SKF-525A, induced changes in embryotoxicity which were well correlated with plasma levels of identified embryotoxic metabolites, but not with the levels of foetal tissue bound drug metabolites.     

Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle

The persistence of the broad-spectrum antiparasitic activity of endectocide compounds relies on their disposition kinetics and pattern of plasma/tissues exchange in the host. This study evaluates the comparative plasma disposition kinetics of ivermectin (IVM), moxidectin (MXD) and doramectin (DRM) in cattle treated with commercially available injectable formulations. Twelve (12) parasite-free male Hereford calves (180–210 kg) grazing on pasture were allocated into three groups of four animals each. Animals in each group received either IVM (Ivomec 1%, MSD AGVET, Rahway, NJ, USA), MXD (Cydectin 1%, American Cyanamid, Wayne, NJ, USA) or DRM (Dectomax 1%, Pfizer Inc., New York, NY, USA) by subcutaneous injection at a dose of 200 μg/kg. Jugular blood samples were collected from 1 h up to 80 days post-treatment, and plasma extracted, derivatized and analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The parent molecules were detected in plasma between 1 h and either 70 (DRM) or 80 (IVM and MXD) days post-treatment. The absorption of MXD from the site of injection was significantly faster (absorption half-life (t_½ab) = 1.32 h) than those of IVM (t_½ab= 39.2 h) and DRM (t_½ab= 56.4 h). MXD peak plasma concentration (C_max) was reached significantly earlier (8.00 h) compared to those of IVM and DRM (4–6 days post-treatment). There were no differences on C_max values; the area under the concentration–time curve (AUC) was higher for IVM (459 ng.d/mL) and DRM (627 ng.d/mL) compared to that of MXD (217 ng.d/mL). The mean plasma residence time was longer for MXD (14.6 d) compared to IVM (7.35 d) and DRM (9.09 d). Unidentified metabolites were detected in plasma; they accounted for 5.75% (DRM), 8.50% (IVM) and 13.8% (MXD) of the total amount of their respective parent drugs recovered in plasma. The comparative plasma disposition kinetics of IVM, MXD and DRM in cattle, characterized over 80 days post-treatment under standardized experimental conditions, is reported for the first time.     

Biliary secretion and enterohepatic recycling of fenbendazole metabolites in sheep

Fenbendazole (FBZ) was administered intraruminally at 5.0 mg/kg, containing a trace of [¹⁴C]-FBZ, to sheep fitted with a permanent bile duct cannula and the behaviour of FBZ and its metabolites examined in bile and plasma. Of the administered radiolabeled dose, 47% was secreted in bile of which 34% was accounted for as conjugated and 4% as unconjugated (free) metabolites. Hydroxylated oxfendazole (OH.OFZ) was the major biliary metabolite contributing 66%, and hydroxy-FBZ (OH.FBZ) 27%, of the total metabolites characterized. Small amounts of OFZ and hydroxy FBZ sulphone (OH. FBZ.SO₂) were also present in bile. The rapid appearance of OH.OFZ in bile, even before maximum concentrations of OFZ occurred in plasma, indicated that sulphoxidation and hydroxylation was the major route of FBZ metabolism.
Following intraduodenal infusion of free biliary metabolites, FBZ and its metabolites rapidly appeared in bile indicating absorption from the small intestine. When conjugated metabolites were infused they continued to appear in bile for a further 15–20 h after cessation of infusion indicating that absorption of hydroxylated metabolites occurred largely after bacterial deconjugation in the large intestine. Approximately 40% of biliary metabolites were estimated to undergo enterohepatic reabsorption but they contributed minimally to the metabolite content in plasma. It is suggested that during the process of recycling, biliary metabolites make substantial contact with parasites in the mucosa of the small and large intestine thereby contributing to the anthelmintic activity of FBZ.     

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.     

Effects of feeding on the plasma disposition kinetics of the anthelmintic albendazole in laying hens

1. To optimise the use of albendazole (ABZ) as an anthelmintic in hens, the effects of fasting and type of diet on the plasma kinetics of ABZ and its metabolites were evaluated.

2. Twenty-four hens were distributed into 4 groups: In experiment I the Fed group were fed ad libitum, while the Fasted group was fasted over a 12-h period. In experiment II the Pelleted group was fed with pelleted commercial food, while the Grain group was fed with cereal grains. All the groups were treated with ABZ by oral route. Blood samples were taken and plasma analysed by HPLC.

3. ABZ and its metabolites albendazole-sulphoxide (ABZSO) and albendazole-sulphone (ABZSO₂) were recovered in plasma in all the groups. The 12-h fasting period did not modify the disposition kinetics of ABZ in hens. The type of feed affected ABZ kinetics. ABZSO concentration profile was higher and detected for longer in the Grain group compared to the Pelleted group. Statistical differences were not found for AUC_0-∞ values, whereas the T_1/2for and T_1/2el were different between groups.

4. Factors affecting ABZ kinetic behaviour should be taken into account to optimise its use to ensure the sustainability of the limited available anthelmintic therapeutic tools in avian parasite control.     

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.     

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.     

Disposition kinetics of albendazole and metabolites in laying hens

Bistoletti, M., Alvarez, L., Lanusse, C., Moreno, L. Disposition kinetics of albendazole and metabolites in laying hens. J. vet. Pharmacol. Therap.  36 , 161–168. An increasing prevalence of roundworm parasites in poultry, particularly in litter‐based housing systems, has been reported. However, few anthelmintic drugs are commercially available for use in avian production systems. The anthelmintic efficacy of albendazole (ABZ) in poultry has been demonstrated well. The goal of this work was to characterize the ABZ and metabolites plasma disposition kinetics after treatment with different administration routes in laying hens. Twenty‐four laying hens Plymouth Rock Barrada were distributed into three groups and treated with ABZ as follows: intravenously at 10 mg/kg (ABZ i.v.); orally at the same dose (ABZ oral); and in medicated feed at 10 mg/kg·day for 7 days (ABZ feed). Blood samples were taken up to 48 h posttreatment (ABZ i.v. and ABZ oral) and up to 10 days poststart feed medication (ABZ feed). The collected plasma samples were analyzed using high‐performance liquid chromatography. ABZ and its albendazole sulphoxide (ABZSO) and ABZSO₂ metabolites were recovered in plasma after ABZ i.v. administration. ABZ parent compound showed an initial concentration of 16.4 ± 2.0 μg/mL, being rapidly metabolized into the ABZSO and ABZSO₂ metabolites. The ABZSO maximum concentration (C_max) (3.10 ± 0.78 μg/mL) was higher than that of ABZSO₂C_max (0.34 ± 0.05 μg/mL). The area under the concentration vs time curve (AUC) for ABZSO (21.9 ± 3.6 μg·h/mL) was higher than that observed for ABZSO₂ and ABZ (7.80 ± 1.02 and 12.0 ± 1.6 μg·h/mL, respectively). The ABZ body clearance (Cl) was 0.88 ± 0.11 L·h/kg with an elimination half‐life (T_1/2el) of 3.47 ± 0.73 h. The T_1/2el for ABZSO and ABZSO₂ were 6.36 ± 1.50 and 5.40 ± 1.90 h, respectively. After ABZ oral administration, low ABZ plasma concentrations were measured between 0.5 and 3 h posttreatment. ABZ was rapidly metabolized to ABZSO (C_max, 1.71 ± 0.62 μg/mL) and ABZSO₂ (C_max, 0.43 ± 0.04 μg/mL). The metabolite systemic exposure (AUC) values were 18.6 ± 2.0 and 10.6 ± 0.9 μg·h/mL for ABZSO and ABZSO₂, respectively. The half‐life values after ABZ oral were similar (5.91 ± 0.60 and 5.57 ± 1.19 h for ABZSO and ABZSO₂, respectively) to those obtained after ABZ i.v. administration. ABZ was not recovered from the bloodstream after ABZ feed administration. AUC values of ABZSO and ABZSO₂ were 61.9 and 92.4 μg·h/mL, respectively. The work reported here provides useful information on the pharmacokinetic behavior of ABZ after both i.v. and oral administrations in hens, which is a useful first step to evaluate its potential as an anthelmintic tool for use in poultry.     

奥芬达唑和阿苯达唑对猪囊尾蚴作用形态学比较观察

观察了奥芬达唑和阿苯达唑对猪体内及体外培养的不同发育阶段囊尾蚴作用的形态学效果.结果表明奥芬达唑具有显著的疗效,优于阿苯达唑,且对未成熟期猪囊尾蚴的杀灭作用优于成熟期.提示奥芬达唑可能成为抗未成熟期猪囊尾蚴及治疗脑囊虫病的有效药物.