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The bioavailability of febantel in dehydrated camels
Abstract
In the present study the bioavailability of febantel paste and febantel suspension was investigated in the fully hydrated and the dehydrated camel. The serum concentrations of febantel and its metabolites, fenbendazole, oxfendazole and fenbendazole sulfone were determined by high performance liquid chromatography following extraction with ether. The exposure to febantel and its metabolites in fully hydrated camels was significantly higher in camels dosed with febantel paste compared to febantel suspension, as measured by AUC and Cmax. The AUC and Cmax of fenbendazole and oxfendazole were significantly lower in dehydrated camels as compared to control camels dosed with febantel paste. The systemic availability of febantel suspension in control and dehydrated camels was very low and differences between dehydration and control phases were insignificant. The low systemic availability of febantel in camels dosed with febantel suspension may cause nematodes to become resistant to this anthelmintic. It is, thus, suggested to increase the dose of febantel paste in dehydrated camels in order to increase the exposure to febantel and its metabolites. The binding of febantel, fenbendazole, oxfendazole and fenbendazole sulfone to camels' serum proteins was over 85%. Oxfendazole was only about 70% bound. Dehydration of 10 days did not affect the binding of these benzimidazole derivatives to serum proteins.
... The metabolic pathway of febantel shows that it gets converted directly to either fenbendazole or oxfendazole, which is achieved via febantel sulfoxide as an intermediate [6]. Febendazole, fenbendazole sulfone, oxfendazole, and oxfendazole sulfone are the main metabolites of febantel [7]. Generally, febantel is administered in combination with other benzimidazoles viz. ...
Background
The aim of the present work was to determine potential toxicity of degradation products of febantel generated under different stress conditions mentioned in guideline Q1A (R2) laid down by International Council for Harmonization (ICH). The stability behavior of febantel was studied by subjecting it to hydrolytic, oxidative, photolytic and thermal forced degradation conditions.
Results
Five degradation products (DPs) were observed which were resolved using high-performance liquid chromatography (HPLC) and characterized by LC-MS/MS using positive mode of electrospray ionization. The chromatographic separation was carried out on Hypersil® BDS C18 (150 × 4.6 mm, 5 μm) column. Optimum resolution was obtained using ammonium formate buffer (10 mM, pH 3.5) and acetonitrile programmed in gradient elution mode at 281.0 nm using photodiode array detector.
Conclusion
The drug was found susceptible to degradation under all the stress conditions except thermal and oxidative stress. Five major unknown degradation products DP–I, DP–II, DP–III, DP–IV, and DP–V generated under photolytic, alkali, and acidic stress condition were identified and characterized by LC-MS/MS. The drug and identified degradation products were screened for prediction of in-silico toxicity using software viz. Swiss ADME, OSIRIS Property Explorer and Pro Tox II which indicated overall no toxicological concerns.
Graphical abstract
Distribution is the process by which a drug leaves the bloodstream and is delivered to body tissues, including the target organ. Diffusion is typically uneven throughout the body, chiefly because of differences in perfusion rate in the various organs and tissues. Once absorbed, most drugs do not spread evenly throughout the body. Hydrophilic drugs tend to stay within the blood and the interstitial space. Hydrophobic drugs tend to concentrate in fatty tissues. Other drugs may concentrate mainly in only one small part of the body if the tissues there have a special attraction for and ability to retain the drug. Regional differences in pH and membrane permeability also play a role in differential distribution. However, in theory, a drug will distribute from the main circulation into capillaries and then equilibrate into extracellular spaces and then intracellular spaces of organs and tissues. This movement of a drug throughout the body occurs through body water compartments after a drug is dissolved and absorbed.
One adult (13-yr-old) and two young (3-4-yr-old) male dromedary camels (Camelus dromedarius) from the Seoul Zoo displayed anorexia and chronic diarrhea for 2 wk. Direct fecal smear examination revealed Trichuris spp. infection. After confirmation of the infection, fenbendazole was orally administered as a suspension; this was repeated two times at 3-wk intervals. A high initial dose (20 mg/kg) was followed by administration at the recommended dose (10 mg/kg). Starting on the day following the first treatment, a large number of adult whipworms were discharged with the feces over a 3-day period. Two young male dromedary camels gradually recovered. However, the adult male dromedary camel developed continuous bloody mucoid diarrhea and died 2 days after treatment. Postmortem examination revealed that numerous whipworms were attached to the mucosa throughout the large intestine.
We examined the efficacy of febantel against the infection of the diclidophorid monogenean Heterobothrium okamotoi in cultured tiger puffer Takifugu rubripes. Febantel is a prodrug of fenbendazole, a benzimidazole drug, which is widely used in the field of veterinary medicine. Febantel was metabolized to fenbendazole, in tiger puffer just like veterinary animals for oral administration. At the doses of 12.5 mg/kg and 25 mg/kg for 5 days, and 50 mg/kg for 3 days, 88%, 96% and 94%, respectively, of mature worms, and 97%, 95% and 97%, respectively, of immature worms were eradicated at 22-23 degrees C. These results suggest that febantel has high anti-H. okamotoi activity.
Conditions under which camels are usually kept are not conducive to parasite transmission; in spite of this a large number of helminth parasites are known to occur in the camel. Most of these infections do not precipitate frank clinical disease; some species, however, are important as aetiological agents of clinical conditions which are often the result of mixed infections. These include the camel stomach worm Haemonchus longistipes. This helminth, either alone or in mixed infections with Trichostrongylus spp., may cause a debilitating and sometimes fatal condition. Other common helminth infections of the camel include onchocerciasis caused by Onchocerca fasciata, Dipetalonema evansi infection, Fasciola hepatica, F. gigantica, Stilezia vittata, Moniezia expansa and larval Echinococcus granulosus. Information available about helminths of the camel is presented and discussed.
N-(2-[2,3-Bis-(methoxycarbonyl)-guanidino]-5-(phenylthio)-phenyl)-2-methoxyacetamide (febantel, Rintal) is a new compound which is highly active against various species of nematodes and cestodes in mice, rats, dogs, sheep and cattle. In sheep and cattle a single oral dose of 5 mg/kg resulted in an almost complete elimination of larval and adult intestinal nematodes as well as Dictyocaulus. The compound was well tolerated by all animals tested.
1. Human hepatic "acid" beta-galactosidase preparations, which had been purified approximately 250-fold, were examined for activities toward 4-methylumbelliferyl beta-galactosylceramide, lactosylceramide, galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosyl-glucosylceramide(GM1-ganglioside) and galactosyl-N-acetylgalactosaminyl-galactosyl-glucosylceramide (asialo GM1-ganglioside). 2. The enzyme was active toward the synthetic substrate, GM1-ganglioside and asialo GM1-ganglioside but was inactive toward galactosylceramide. Under our assay conditions, optimized for lactosylceramidase II, the preparations were as active toward lactosylceramide as toward GM1-ganglioside or its asialo derivative. The apparent Km values for the three natural substrates were similar. When determined by the assay system of Wehger, D.A., Sattler, M., Clark, C. and McKelvey, H. (1974) Clin. Chim Acta 56, 199-206, lactosylceramide-cleaving activity was 0.2% of that determined by our assay system. This confirmed our previous suggestion that the Wenger assay system determines exclusively the activity of lactosylceramidase I, which is probably identical with galactosylceramide beta-galactosidase. 3. Crude sodium taurocholate was far more effective than pure taurocholate in stimulating hydrolysis of the three glycosphingolipids by the beta-galactosidase. However, crude taurocholate could largely be replaced by smaller amounts of sodium taurodeoxycholate, suggesting that the unique activating capacity of the crude taurocholate might be due to taurodeoxycholate present as the major impurity. 4. Cl- was generally stimulatory for hydrolysis of the natural glycosphingolipids by our enzyme preparation. Effects of additional oleic acid and Triton X-100 were generally minor in either direction. 5. When the enzyme preparation was diluted with water, activity toward the synthetic substrate declined rapidly while those toward the natural substrates were essentially stable. Activity toward the synthetic substrate remained much more stable when the enzyme was diluted with 0.1 M sodium citrate/phosphate buffer, pH 5.0. 6. These observations provide insight into the complex relationship among the human hepatic beta-galactosidases.
Groups of parasite-free lambs and calves which were either housed and fed hay and concentrates or were grazing on pasture were dosed separately with the oral anthelmintics fenbendazole and ivermectin (lambs only). The plasma concentrations of the drugs and their major metabolites were monitored during the period of their metabolism and excretion. The peak plasma concentrations and the availability of the drugs, as estimated by the areas under the plasma concentration-time curves, were significantly less in the grazing animals. When similar groups of lambs were dosed orally with the inert marker chromium EDTA, which has a particle size similar to the anthelmintics, it was observed that a higher percentage of chromium was excreted by the grazing lambs during the first 40 hours after dosing, suggesting that the extent of absorption in the grazing animals was less than in the housed animals.
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.
1. Dehydration of camels for 10 days resulted in reduction of liver functions, expressed in longer half life and reduced clearance of bromosulfophthalein (BSP), elevated AST (ALT levels were below the limit of detection of the method) and reduced serum albumin concentrations. 2. Binding of BSP to camel serum proteins by gel permeation chromatography and by equilibrium dialysis showed very strong binding. 3. Binding parameters of various drugs to camels serum by equilibrium dialysis showed close similarities both qualitatively and quantitatively to those of humans. 4. Albumin seems to be the major serum binding protein of BSP.
There is a cyclical pattern of motility in compartments 1 and 2 of the forestomach of the camel which can be categorized into A- and B-contractions. An average motility cycle is composed of 7 A- and 5 B-contractions and lasts 5 min, including a pause of 2.3 min. The glandular sacs within the caudal sac of compartment 1 contract 1.7 sec earlier than the caudal sac. The proximal part of the canal between compartment 2 and 3 contracts 1.2 sec prior to the distal part. Forestomach motility is stimulated by distention of the cranial sac of compartment 1 and inhibited by distention of the tubiform portion of compartment 3.
Short, C.R., Flory, W., Hsieh, L.C. & Barker, S.A. The oxidative metabolism of fenbendazole: a comparative study. J, vet. Pharmacol. Therap. 11, 50–55.
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-S02), 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 25oC and 37oC incubation temperatures. The formation of the sulfone metabolite (FBZ-SO2), however, was practically nonexistent in catfish.
The α 2 ‐adrenoceptor agonist, clonidine, reduces the hepatobiliary clearance of the anionic dye, sulphobromophthalein (BSP) in rodents. We now compare the effects of clonidine on BSP elimination with its effects on disposition of compounds which are metabolized by hepatic microsomal mixed function oxidases.
BSP, 100 mg kg ⁻¹ was administered i.v. to rats at 4h after s.c. saline or clonidine, 0.2 mg kg ⁻¹ . Thirty min later, plasma BSP levels were 121.4 ± 2.25 μg ml ⁻¹ in saline‐treated rats, while in clonidine‐treated rats they were 631.5 ± 141.0 μg ml ⁻¹ . Clonidine raised hepatic BSP levels from 256.0 ± 28.9 μg g ⁻¹ tissue to 568.5 ± 86.5 μg g ⁻¹ .
Acute administration of clonidine (0.2 mg kg ⁻¹ s.c.) or repeated clonidine dosing (0.2 mg kg ⁻¹ , s.c. twice daily for 10 days) did not affect the disposition of intravenously administered [ ¹⁴ C]‐antipyrine (15 mg kg ⁻¹ ).
Activities of the P450 mixed function oxidase enzymes, aniline hydroxylase and aminopyrine N‐demethylase, were identical in liver microsomes from saline‐treated rats and in microsomes from rats given single or multiple s.c. doses of clonidine (0.2 mg kg ⁻¹ ).
Addition of clonidine or other 2‐substituted imidazoles at concentrations up to 2 μ m did not affect the activities of aniline hydroxylase or of aminopyrine N‐demethylase in suspensions of rat liver microsomes. Other substituted imidazoles, including cimetidine, clotrimazole and metronidazole, at concentrations of 0.2 μ m or higher, inhibited the activities of these microsomal enzymes.
Clonidine slowed BSP elimination, which is probably hepatic blood flow‐limited, but not the extraction‐limited elimination of antipyrine, which is metabolized by hepatic microsomal enzymes.
Hennessy, D.R., Lacey, E., Steel, J.W. & Prichard, R.K. The kinetics of triclabendazole disposition in sheep. J. vet. Pharmacol. Therap. 10, 64–72.
To investigate whether the disposition of triclabendazole (TCBZ) and its metabolites in blood or bile influenced its flukicidal potency, TCBZ was administered intraruminally at 10 mg kg-1 to sheep surgically fitted with a permanent re-entrant bile duct cannula. The profiles of TCBZ metabolites in peripheral plasma and bile were determined using high performance liquid chromatography.
In plasma, only TCBZ sulphoxide (TCBZ-SO) and TCBZ sulphone were present and reached their maximum concentrations (> 13 μg ml-1) at 18 and 36 h, respectively, after administration. TCBZ metabolites were specifically bound to plasma albumin, which is believed to exert a major influence on the duration of plasma TCBZ metabolite concentrations and consequent exposure of liver fluke.
In bile, the major TCBZ metabolites were hydroxylated in the 4'position and secreted predominantly as sulphate esters with lesser proportions as glucuronide conjugates. The major biliary metabolite was conjugated hydroxy TCBZ-SO which reached a maximum concentration in excess of 40 μg ml-′ and contributed almost half the total conjugated metabolites. The major free biliary metabolite was TCBZ-SO. Of the administered TCBZ dose, 9.7% was secreted as free metabolites in bile whereas 35.8% was secreted as conjugated metabolites. Approximately 6.5% of the dose was excreted in urine.
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.
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.
Febantel and one of its main metabolites, febantel sulphoxide, are chemically modified to only a slight extent when incubated in vitro with sheep and cattle ruminal fluids; other major metabolites, fenbendazole and oxfendazole, are respectively, oxidized to oxfendazole and reduced to fenbendazole. Febantel is negligibly metabolized by hepatic cytosol fractions but microsome preparations effect more extensive metabolic transformations. Important differences in this respect were found between microsome preparations from rat, horse, pig, cattle, sheep, chicken and trout livers.
Plasma and abomasal fluid concentrations of fenbendazole and its two major metabolites in sheep experimentally infected with Ostertagia circumcincta were compared with those in the same sheep when non-parasitised. Bio-availability of the drug was reduced in the parasitised state. There was also a reduction in the proportion of drug present in the form of metabolites in parasitised as compared with non-parasitised animals.
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.
The pathogenesis and clinical signs of Haemonchus longistipes infection were studied in four experimentally infected camels two of which were adults and the other two were young. In the former animals, an acute infection developed, characterized by mucoid diarrhoea, anorexia, anaemia, loss of body weight, oedema of the lower parts of the limbs, general malaise and death at 8-10 weeks post-infection. In the two younger camels, a less dramatic disease was encountered with less severe symptoms and no oedema, but also terminating fatally at 19-20 weeks post-infection. Parasitological, haematological and biochemical parameters were determined during the course of the infection and were mostly comparable with those usually encountered in haemonchosis of other animals.
The metabolism of febantel has been investigated in the rat and the sheep. The general pathway seems to be similar in both species: ten urinary metabolites are the result of cyclisation, oxidation and/or hydrolysis process. Using synthetic samples, the embryotoxic study of all individual metabolites has been performed in the rat. Unchanged febantel and two other metabolites are responsible for teratogenic effects. A four steps toxogenic pathway is described which finally leads to the ultimate known teratogen: methyl (5-(phenylsulfinyl)-1H-benzimidazole-2-yl) carbamate. Metabolic similarities with other anthelmintics and residual consequences are discussed.
Three mean particle sizes of oxfendazole raw material (1.65 micron, lot A; 3.2 micron, 10t B; 12.0 micron, lot C) were prepared and identically formulated as corresponding (A, B, and C) suspensions at 2.26% (W/V) concentration. Studies involving microscopic examination, scanning electron microscope analysis, particle size distribution, and surface area measurement were carried out on raw materials. In vitro dissolution profiles were obtained for the suspensions. A comparative bioavailability study of these 3 suspensions was performed in 12 sheep with each sheep given each formulation in a Latin square crossover study design; oxfendazole was dosed at rate of 5 mg/kg of body weight. Plasma-value measurements were made followed by an analysis of various bioavailability studies. Plasma area values indicated that suspension C (dw = 12.0 micron) was significantly (P less than 0.05) less bioavailable than was suspension A (dw = 1.65 micron); there was no difference between suspension A and suspension B. Significant differences were not seen in biological half-life and maximum plasma concentrations. The term dw refers to that particle diameter (determined by Coulter counting) at which 50% of the oxfendazole mass was in the form of particles having a lesser diameter and 50% was in the form of particles having a greater diameter. In a separate study involving 20 Merino weaner sheep infected with benzimidazole-resistant Haemonchus contortus larvae, oxfendazole's anthelmintic efficacy was demonstrated in the 2.26% suspension dosage form (90% particles less than 10 micron) at a dosing rate of 5 mg/kg. A correlation was found between its anthelmintic activity and plasma area values when compared in individual sheep. Data demonstrated that substantial differences in particle size distribution of oxfendazole could influence its dissolution rate, plasma concentrations, and absorption characteristics, thus indicating that oxfendazole's absorption could be dissolution-rate limited.
In the present study the effects of water deprivation in the camel (Camelus dromedarius) on the pharmacokinetic profile of antipyrine were assessed. A cross-over design was used. The pharmacokinetics of antipyrine in adult and young camels were compared. Antipyrine was administered intravenously to young and adult female camels when water was available ad libitum and to the adult camels after 14 days of dehydration. The elimination half-life of antipyrine in watered adult camels was 136.5 +/- 16.7 min. The half-life of elimination and the mean residence time of antipyrine were significantly prolonged following dehydration. The observed effects of water deprivation were not a function of age, as the pharmacokinetic profile of antipyrine in young camels was similar to that of the adults, but more likely due to the changes in oxidative metabolic capacity of the liver as a result of a reduced general metabolism. The results of the present study also show that the intrinsic clearance of antipyrine is proportional to the camel's body weight, as previously shown for other mammalian species.
Two main nematode parasites, Haemonchus longistipes and Trichostrongylus colubriformis, have been reported to cause morbidity and mortality in camels. Although goats are usually reared with camels in the combined animal husbandry system prevailing in Northern India, these parasites have not been reported in goats. Therefore, it was planned to conduct an experimental cross-transmission study of H. longistipes and T. colubriformis isolated from camels and transferred to young goats. Twelve healthy kids (5-6 months) were divided into three groups of four each. Groups I and II were infected orally with third stage infective larvae of H. longistipes and T. colubriformis cultured in the laboratory from faecal isolates from camels, at the rate of 50,000 and 100,000 larvae, respectively; group III comprised uninfected healthy controls. Daily clinical and faecal examinations were made. Body weights and blood haematological indices were measured at weekly intervals. The infection became established in both infected groups, and the animals started passing ova 17 days postinfection. Egg counts varied from 275.00 +/- 248.74 to 6150 +/- 2830.63 eggs g-1. Animals were killed 28 days postinfection. On postmortem examination mature as well as immature worms were recovered from the abomasum and intestine with typical postmortem changes seen in both the groups. Clinical manifestations were weakness and loss of body weight but no diarrhoea. There was a marked fall in haemoglobin and packed cell volume, indicating anaemia in both infected groups.
Despite the enormous advances over the last 50 years in the chemotherapeutic control of nematode parasites, the economic importance of these parasites to the grazing livestock industries remains as great as ever. Added to this, the emergence and rapid development of resistance to the new broad spectrum anthelmintics in the important nematode species now looms large as a major international threat. This particularly is of concern to the sheep industry, especially in the major sheep-raising countries of the Southern Hemisphere, but there are clear signs that the problem in Western Europe and North America is rapidly escalating. Resistance is also a serious concern in the intensive goat industry, but at present appears to occur only on isolated, individual cattle properties. To obtain a perspective of the development of anthelmintic resistance in relation to husbandry practices, this review focuses on the problem in the sheep industry in relation to its development, detection and management.
The kinetic and dynamic disposition of endo- and ectoparasiticides in livestock in relation to development of resistance is examined. Based on the modes of action of antiparasitic drugs, maximum activity necessitates that the parasite be exposed to 'toxic' concentrations for as great a duration as possible. In contrast, exposure to non-lethal discriminating drug concentrations has a significant potential to promote the development of resistance. Orally administered anthelmintics quickly associate with particulate digesta in the rumen; their subsequent desorption from particulate matter as it vacates the rumen maintains the duration of metabolite availability. The flow rate of digesta increases with feed intake and the presence of gastrointestinal parasites, and together with other parasite-induced physiological changes to the gut, contributes to reduced duration of drug availability. The potential for orally administered drugs to bypass the rumen, due to closure of the oesophageal groove, exacerbates the effect. Once absorbed, the metabolite concentration with time profile progressively decreases, the rate depending upon the chemical nature of the drug and the type and condition of the host into which it was administered. The greater hepatic activity of goats speeds drug elimination, the lower dose equivalent availability increases the potential for generation of drug resistance in parasites of goats as compared to sheep. Parasites whose resistance is generated in goats may be then transferred to sheep. Similar distribution/elimination kinetics apply to topically administered insecticides of sheep. The progressively reducing concentrations expose ectoparasites to discriminating drug levels, again contributing to the development of resistance. It is anticipated that a greater understanding of the physiological/pharmacological effects which are described in this review will permit the more efficient use of existing and future antiparasitic drugs.
Plasma concentrations of febantel and its major metabolites fenbendazole, oxfendazole and oxfendazole sulphone were determined after oral administration of 7.5 mg/kg febantel in lambs before and 28 days after infection with 50 000 L3 larvae of Ostertagia circumcincta or Trichostrongylus colubriformis. The febantel concentrations were always very low and only in a few samples higher than the detection limit. The mean decrease in AUC for the three metabolites for the infected sheep in comparison to the parasite naive sheep was 13.9%± 4.1% (mean± SEM) and 23.7%± 5.3% in the 0. circumcincta infected and the T. colubriformis infected lambs respectively. This reduction was only significant for the T. colubriformis infected group.
In order to determine a more complete pharmacokinetic profile, febantel was injected intravenously at a dose of 2.5 mg/kg in a further study.
The kinetic disposition of [14C]-oxfendazole (OFZ) and its metabolites, fenbendazole (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 micrograms.h/ml) than in sheep (22.2 micrograms.h/ml) and was reduced with infection in goats (5.6 micrograms.h/ml) and sheep (15.1 micrograms.h/ml). The elimination of plasma [14C] 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.
A high performance liquid chromatographic (HPLC) method for the determination of the anthelminthic pro-benzimidazole febantel and its major metabolites in lamb plasma has been developed. Samples were extracted after addition of albendazole as internal standard, NH4OH and distilled diethyl ether. The extracted phase was dried under a stream of nitrogen redissolved in methanol and chromatographed by HPLC. Detection was by UV absorbance at 292 nm. Recovery from the plasma was 97.2, 97.1, 54.5 and 88.0% for febantel, fenbendazole, oxfendazole and oxfendazole sulphone respectively, and within-day and between-day coefficients of variation were 4.03, 4.69, 3.57 and 5.06% and 4.25, 3.73, 5.12 and 4.12%, respectively, for febantel, fenbendazole, oxfendazole and oxfendazole sulphone. The specificity and sensitivity of this method (limit of detection in plasma 0.025 micrograms/mL and < or = 0.0125 micrograms/mL for febantel and its metabolites, respectively) were sufficiently high to enable us to characterize the time course of the drug in the plasma after oral administration of therapeutic doses to sheep.
A rapid and reliable method for measuring serum albumin employing bromcresol green is described. The addition of albumin to a solution of bromcresol green in a 0.075 M succinate buffer pH 4.20 results in an increase in absorbance at 628 nm. The absorbance-concentration relationship is linear for samples containing up to 6 g/dl albumin. Bilirubin, moderate lipemia, and salicylate do not interfere with the analysis. The use of nonionic surfactant (Brij-35) reduces the absorbance of the blank, prevents turbidity and provides linearity. The results by this method agree very well with those obtained by electrophoresis and salt fractionation. The method is simple, it has excellent precision and the reagents are stable. A protein standard is introduced which can be employed for both the total serum proteins and albumin determinations.
Since 1922 when Wu proposed the use of the Folin phenol reagent for
the measurement of proteins (l), a number of modified analytical pro-
cedures ut.ilizing this reagent have been reported for the determination
of proteins in serum (2-G), in antigen-antibody precipitates (7-9), and
in insulin (10).
Although the reagent would seem to be recommended by its great sen-
sitivity and the simplicity of procedure possible with its use, it has not
found great favor for general biochemical purposes.
In the belief that this reagent, nevertheless, has considerable merit for
certain application, but that its peculiarities and limitations need to be
understood for its fullest exploitation, it has been studied with regard t.o
effects of variations in pH, time of reaction, and concentration of react-
ants, permissible levels of reagents commonly used in handling proteins,
and interfering subst.ances. Procedures are described for measuring pro-
tein in solution or after precipitation wit,h acids or other agents, and for
the determination of as little as 0.2 y of protein.
Rate of passage of digesta through the gut of mammal and birds We are grateful to the Slome family for their financial support of the research The etrect of feed type on pharmacokinetic disposition of oxfendazole in sheep
- A C I Warner
Warner, A.C.I. (1981) Rate of passage of digesta through the gut of mammal and birds. Nutrition Abstracts and Reviews, 51, 789 820. 56, 125-141. 204-209. We are grateful to the Slome family for their financial support of the research. REFERENCES Ali, D.N. & Chick, B.F. (1992) The etrect of feed type on pharmacokinetic disposition of oxfendazole in sheep. Research in Veterinary Science, 52, Arzoun, LH.. Hussein, H.S. & Hussein, M.F. (1987) The pathogenesis of experimental Haemonchus longistipes in camels. Veterinary Parasitology.
Helminths in the camel
- El S Bdhari
El Bdhari. S. (1985) Helminths in the camel. British Veterinary Journal, Gibaldi. M. 81 Perrier D. (1982) Pharmacokinetics 2nd edn. pp. 445449. Marcel Dekker Inc. New York.
The disposition of antiparasitic drugs in relation to the development of resistance by parasites of livestock A high performance liquid chromatographic method for determination of febantel and its major metabolites in lambs plasma
- D R Hennessy
Hennessy. D.R. (1994) The disposition of antiparasitic drugs in relation to the development of resistance by parasites of livestock. Acta Tropica, Landuyt. J., Debackere M.. Delbeke. F. & McKeUar, Q.A. (1993) A high performance liquid chromatographic method for determination of febantel and its major metabolites in lambs plasma. Biomedical Chromatography. 7, 78-81.
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