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.     

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     

Pharmacokinetics and metabolism of fenbendazole in channel catfish

Fenbendazole (FBZ) was administered intravenously (1 mg/kg) and orally (5 mg/kg) to catheterized, confined channel catfish. Blood samples were collected for 72 h, and resulting FBZ plasma concentrations were pharmacokinetically modelled. Following intravenous administration t1/2 was 0.51 h, t1/2 was 16.8 h, body clearance (C1b) was 0.0598 L/kg/h, and Vd (area) was 1.45 L/kg. After oral administration the t1/2 (abs) was 1.47 h, the t1/2 was 20.1 h, and the tlag was 0.1 h.Following oral administration of 5 mg FBZ/kg body weight, the following tissues and body fluids were sampled for concentrations of FBZ, oxfendazole (FBZ-SO), sulphone metabolite (FBZ-SO₂) and hydroxy metabolite (FBZ-OH): liver, posterior kidney, fat, muscle, bowel contents and urine. Fenbendazole was detected in the highest concentrations in abdominal fat, whereas oxfendazole was found primarily in the kidney, liver and abdominal fat. The sulphone metabolite was detected only in urine and bowel contents, while the hydroxy metabolite was found most often in the liver and abdominal fat samples.     

The oxidative metabolism of fenbendazole: a comparative study

The oxidative metabolism of fenbendazole (FBZ) was studied in hepatic fractions prepared from livers of cattle, sheep, goats, chickens, ducks, turkeys, rats, rabbits and catfish. All species produced the sulfoxide metabolite (oxfendazole; FBZ-SO), and p-hydroxyfenbendazole (FBZ-OH) was produced by all species except sheep. The product of demethoxycarbonylation, fenbendazole amine (FBZ-NH2), was not produced by liver preparations of any species. A fourth metabolite, resulting from the further oxidation of oxfendazole, fenbendazole sulfone (FBZ-SO2), was formed in all species but at highly varying rates. The chicken exhibited the highest overall rate of FBZ metabolism, followed by the duck, goat, sheep, steer, catfish, rat, rabbit, and turkey. Considerable variation was evident among avian species, the duck and turkey produced substantially less of the FBZ-OH and FBZ-SO2 metabolites than the chicken. Catfish liver preparations formed equivalent amounts of metabolite at 25 degrees C and 37 degrees C incubation temperatures. The formation of the sulfone metabolite (FBZ-SO2), however, was practically nonexistent in catfish.     

Fenbendazole-related drug residues in milk from treated dairy cows

Oral administration of [¹⁴C] fenbendazole (FBZ) at a dose of 5.Omg/kg leads to the presence of radiolabel in the milk of lactating dairy cows. However, the maximum mean concentration of total FBZ equivalents quantitated to one-third of the recommended safe concentration in milk (1.67 μg/mL). The label is equally distributed to the fat and aqueous portions of the milk. The maximum level, in general, is attained approximately 24-36 h after drug administration, with the highest levels ranging from 24 to 48 h after administration. The residues rapidly deplete, attaining levels of 10-20ng/mL by day 5, and are essentially undetectable by radiolabel monitoring by day 6. Extraction of the milk by matrix solid phase dispersion indicated that the label was distributed between traces of the parent drug, FBZ, and predominantly, the FBZ sulphoxide (SO) and sulphone (SO₂) metabolites. No other radiolabelled peaks were observed. Based on these data the metabolites of FBZ, FBZ-sulphone and FBZ-sulphoxide, could be used as marker residues for monitoring the administration of FBZ to lactating dairy cows.     

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.     

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.     

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.     

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

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

Plasma 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.     

苦参碱对昆明小鼠粪便及血浆代谢物的影响

基于非靶向代谢组学技术,分析腹腔注射苦参碱前后昆明小鼠粪便和血浆代谢物的差异,并通过与此前16S rDNA测序结果联合分析探究苦参碱发挥药理作用的可能机理。将20只昆明小鼠随机分为2组,分别是苦参碱处理组(MT)和生理盐水处理组(NC)。苦参碱处理组每天腹腔注射40 mg·kg^-1的苦参碱,连续给药5 d,每天给药2次。生理盐水处理组按照同样方式和体积腹腔注射生理盐水。给药第6天,分别收集各组小鼠的粪便和血浆,进行非靶向代谢组学检测,并与苦参碱处理组肠道菌群的16S rDNA测序结果进行联合分析。苦参碱处理组的粪便及血浆中均存在显著差异代谢物,粪便中共鉴定出97种,血浆中有44种。聚类分析显示,粪便中苦参碱组有35种代谢物上调,104种代谢物下调;血浆中苦参碱组有20种代谢物上调,35种代谢物下调。KEGG通路分析显示粪便及血浆差异代谢物被映射到Protein digestion and absorption等代谢途径。与16S rDNA测序分析得到的显著差异菌种嗜酸乳杆菌关联分析,结果表明粪便及血浆代谢物与嗜酸乳杆菌存在相关性。苦参碱可调节昆明小鼠的体内代谢,在粪便和血浆中均存在显著差异代谢物。这些差异代谢物及与菌群之间的互作可能是其发挥药理作用的关键。     

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.     

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.     

恩诺沙星及其代谢物环丙沙星在猪粪便及尿液中的排泄研究

给猪连续3d饲喂含无味恩诺沙星的饲料后，对其排泄的粪便和尿液进行了药物含量测定结果表明，粪便和尿液中恩诺沙星及其代谢产物环丙沙星的排泄量都比较高，粪便中排泄的药物浓度显著高于尿液中药物排泄的浓度，停止给药后第15天，在猪粪中可检测到恩诺沙星，停止给药后第10天，猪尿液中可检测到环丙沙星。     

Effect of Fenbendazole on Turkey Semen Quality

Fenbendazole (FBZ) is an anthelmintic recently approved to treat and control nematode infections in growing turkeys. When administered to growing turkeys there are no detrimental side effects. However, when we used FBZ to treat nematodes in mature breeder toms, we observed a decrease in semen quality and a subsequent precipitous decline in fertility to less than 20% within 6 wk of administration. An experiment was designed to determine the impact of FBZ administration on aspects of spermatogenesis and semen quality. We discovered that although sperm viability and concentration was not significantly affected by FBZ, this drug significantly reduced sperm mobility. However, normal mobility resumed within 6 wk after FBZ administration. Fenbendazole binds to tubulin and interferes with microtubule assembly. Based on testes histology and the immunocytochemical localization of tubulin in spermatids and mature sperm, FBZ had no affect on any aspect of spermatogenesis. We suggest that FBZ may be affecting sperm mobility by some molecular alteration of the sperm tail axoneme or midpiece, both of which are tubulin-containing structures. If a breeding flock of toms become infected with nematode parasites, a flock manager has the following options: do not treat the toms, find an alternative to FBZ, treat the toms with FBZ and increase the sperm number and frequency of artificial inseminations, or treat the toms with FBZ and secure semen from an uninfected tom flock.     

Characterization and tissue distribution of conjugated metabolites of pyrene in the rat

Pyrene (PY) is a polycyclic aromatic hydrocarbon (PAH) that is often used as a biomarker for human and wildlife exposure to PAHs. As the metabolites of PAHs, similar to their parent compounds, pose public health risks, it is necessary to study their characteristics and tissue-specific distribution. The present study was performed to experimentally characterize PY metabolites and analyze the tissue-specific distribution of the conjugated metabolites after oral administration of PY to rats. PY metabolites, such as pyrenediol-disulfate (PYdiol-diS), pyrenediol-sulfate (PYdiol-S), pyrene-1-sufate (PYOS), pyrene-1-glucuronide (PYOG) and 1-hydroxypyrene (PYOH), were detected in rat urine. Although glucuronide conjugate was the predominant metabolite, the metabolite composition varied among tissues. Interestingly, the proportion of PYOH was high in the large intestine. Furthermore, PYOH was the only PY metabolite detected in feces.     

Disposition of cyadox in domesticated cats following oral,intramuscular, and intravenous administration

Cyadox (CYX) is a synthetic antibacterial agent of quinoxaline with much lower toxic effects. A safety criterion of CYX for clinical use was established by studying the pharmacokinetics and metabolism of CYX after oral (PO), intramuscular (IM), and intravenous (IV) administration. CYX was administered in six domesticated cats (three males and three females) by PO (40 mg/kg.b.w.), IM (10 mg/kg.b.w.), and IV (10 mg/kg.b.w.) routes in a crossover pattern. Highly sensitive liquid chromatography with ultraviolet detection (HPLC-UV) method was developed for detection of CYX and its metabolites present in plasma, urine, and feces. The bioavailability of CYX after PO and IM routes was 4.37% and 84.4%. The area under curves (AUC), mean resident time (MRT), and clearance (CL) of CYX and its metabolites revealed that CYX quickly metabolized into its metabolites. The total recovery of CYX and its main metabolites was >60% after each route. PO delivery suggesting first pass effect in cats that might make this route suitable for intestinal infection and IM injection could be better choice for systemic infections. Less ability of glucuronidation did not show any impact on CYX metabolism. The findings of present study provide detailed information for evaluation of CYX.     

The pharmacokinetics, metabolism and urinary detection time of etamiphylline in camels after intramuscular administration

The pharmacokinetics of etamiphylline were determined after an intramuscular (i.m.) dose of 3.5 mg/kg body weight in six healthy camels. Furthermore, the metabolites and drug detection time were evaluated. The data obtained median and (range) were as follows: the terminal elimination half-life (t(1/2 beta), h) was 3.04 (2.03-3.62); apparent total body clearance (Cl/F, L/h/kg) was 1.27 (0.74-2.99); the apparent volume of distribution at steady state (V(ss)/F, L/kg) was 4.94 (3.57-12.54); and renal clearance (Cl(r), L/h/kg) determined in two camels was 0.005 and 0.004, respectively. The detection time of etamiphylline in urine after an i.m. dose of 3.5 mg/kg body weight ranged between 12 and 13 days. Three etamiphylline metabolites were tentatively identified in camels urine: The first one desethyletamiphylline was the main metabolite and resulted from N-deethylation of etamiphylline had a molecular weight of 251, and was detected in urine for about 13-14 days. Theophylline (molecular weight 180) was the second metabolite and resulted from ring N-dealkylation of etamiphylline. It was present in small amounts and was detected for about 5 h after drug administration in urine. The third metabolite, possibly resulted from demethylation of etamiphylline, had a molecular weight of m/z 265, and was present in small amounts and was detected in urine for about 5 h after drug administration.     

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.