The partition and fate of soluble and digesta particulate associated oxfendazole and its metabolites in the gastrointestinal tract of sheep

doi:10.1016/0020-7519(94)90079-5

International Journal for Parasitology

Volume 24, Issue 3, May 1994, Pages 327-333

https://doi.org/10.1016/0020-7519(94)90079-5 Get rights and content

Abstract

The disposition of oxfendazole (OFZ) containing a trace of [¹⁴C]OFZ was examined in the gastrointestinal tract and bloodstream of sheep fitted with rumen and abomasal cannulae. Within 2 h of intraruminal (IR) administration, OFZ and its metabolites were almost completely associated with rumen particulate digesta. The proportion of metabolites in digesta fluid increased with their passage from the rumen into the abomasum. To determine the fate of ¹⁴C-labelled metabolites after distribution throughout rumen digesta, the rumen particulate and fluid digesta phases from a donor sheep were separated and each transferred to the rumen of an untreated recipient sheep. The ¹⁴C-labelled metabolites which derived from the donor rumen fluid quickly associated with recipient rumen particulate material. The metabolites were then progressively desorbed, as were metabolites which were transferred already associated with rumen particulate digesta. Desorption occurred faster in the abomasum than in the rumen. There was no difference in uptake kinetics between administration routes, indicating rapid equilibrium. Consequently the disposition of [¹⁴C] OFZ and its metabolites in the bloodstream was similar in each group. It is suggested that the progressive desorption of particulate associated metabolites is a principal determinant of the duration of OFZ availability.

References (28)

G.J. Faichney et al.
A simple technique to establish a self-retaining rumen catheter suitable for long-term infusions
Research in Veterinary Science
(1979)
E. Lacey
The role of the cytoskeletal protein, tubulin, in the mode of action and mechanism of drug resistance to benzimidazoles
International Journal for Parasitology
(1988)
R.K. Prichard et al.
Effect of oesophageal groove closure on the pharmacokinetic behaviour and efficacy of oxfendazole
Research in Veterinary Science
(1981)
N.C. Sangster et al.
Disposition of exfendazole in goats and efficacy compared with sheep
Research in Veterinary Science
(1991)
T.N. Tan et al.
Use of ¹⁰³Ru labelled Tris-(1,10-phenanthroline) ruthenium (11) chloride as a marker in digestion studies with sheep
International Journal of Applied Radiation and Isotopes
(1971)
E.A. Averkin et al.
Methyl 5(6)-phenylsulfinyl-2-benzimidazolecarbamate, a new, potent anthelmintic
Journal of Medicinal Chemistry
(1975)
J.A. Bogan et al.
The rumen as a pharmacokinetic compartment
R.D. Brown et al.
Estrip, a BASIC computer program for obtaining initial polyexponential parameter estimates
Journal of Pharmaceutical Sciences
(1978)
J.B. Coombe et al.
Passage of digesta through the intestines of the sheep, retention times in the small and large intestines
British Journal of Nutrition
(1965)
P. Costigan et al.
Analysis of faecal chromium derived from controlled release marker devices
New Zealand Journal of Technology
(1987)

D. Düwel

Fenbendazole: II Biological properties and activity

Pesticide Science

(1977)

G.J. Faichney

The use of markers to partition digestion within the gastro-intestinal tract of ruminants

G.J. Faichney

Application of the double-marker method for measuring digesta kinetics to rumen sampling in sheep following a dose of the markers or the end of their continuous infusion

Australian Journal of Agricultural Research

(1992)

M. Gibaldi et al.

Pharmacokinetics

Drugs and the Pharmaceutical Sciences

(1982)

Cited by (42)

Combination of bioactive phytochemicals and synthetic anthelmintics: In vivo and in vitro assessment of the albendazole-thymol association
2020, Veterinary Parasitology
Citation Excerpt :
To evaluate the relative partition of TML between the fluid and solid phases of ruminal contents, TML was incubated in ruminal content for 30, 120 and 240 min as described above. From each incubation vial, 0.5 mL was taken and centrifuged at 18 000 g for 8 min to separate the solid (particulate) and fluid phases of the ruminal content (Hennessy et al., 1994). Both phases were frozen at −20 °C until drug extraction.
The search of novel strategies for anthelmintic control is a crucial need considering the widespread increase in resistant parasitic populations in livestock. Bioactive phytochemicals may contribute to improve parasite control by enhancing the effect of existing anthelmintic drugs. The aim of the current work was to evaluate the in vivo and in vitro pharmaco-chemical interaction and the in vivo efficacy of the combination of albendazole (ABZ) with thymol (TML) in lambs naturally infected with resistant gastrointestinal nematodes. Thirty (30) lambs were allocated into three experimental groups. Each group was treated orally with either ABZ (5 mg/kg), TML (150 mg/kg, twice every 24 h) or the co-administration of both compounds. Blood samples were collected between 0 and 51 h post-treatment and TML, ABZ and its metabolites were measured by HPLC. Individual faecal samples were collected at days -1 and 14 post-treatment to perform the faecal egg count reduction test. Additionally, the effect of TML on the sulphoreduction and sulphonation of ABZ sulphoxide was assessed in vitro using ruminal content and liver microsomes, respectively. The metabolism of TML in the ruminal content was very low and the monoterpene exhibited a low degree of association with the particulate phase of the ruminal content. No changes in the pharmacokinetic behavior of ABZ sulphoxide were observed in the presence of the natural product (TML). In contrast, the ABZ sulphone Cmax and AUC were lower (P 0.002 and 0.001 respectively) in the co-administered animals (0.16 ± 0.07 μg/mL and 3.63 ± 1.21 μg.h/mL) compared with those that received ABZ alone (0.45 ± 0.15 μg/mL and 9.50 ± 2.84 μg.h/mL). TML was detected in the bloodstream between 1 and 48 h post-treatment, which indicates the time of target nematodes being exposed to the bioactive monoterpene. However, the in vivo efficacy of TML was 0% and the presence of this terpene did not increase the efficacy of ABZ. The presence of TML significantly inhibited the ruminal sulphoreduction (P 0.001) and the hepatic sulphonation (P 0.001) of ABZ sulphoxide. These observations point out that in vivo pharmaco-parasitological studies are relevant to corroborate the adverse kinetic/metabolic interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics.
Efficacy of oxyclozanide against adult Paramphistomum leydeni in naturally infected sheep
2014, Veterinary Parasitology
Citation Excerpt :
The association of the drug with rumen digesta cellulose limited the amount of “free” drug in the ruminal fluid. In fact, the extensive association of oxfendazole (Hennessy et al., 1994), closantel (Hennessy and Ali, 1997) and ivermectin (Lifschitz et al., 2005) with rumen digesta cellulose have been reported. Closantel, another salicylanilide compound, was almost completely (99%) associated with rumen particulate material with minimal amount in rumen digesta fluid (Hennessy and Ali, 1997).
The aim of the current study was to assess oxyclozanide (OCZ) efficacy against Paramphistomum leydeni in naturally infected adult sheep. OCZ concentrations in blood stream and gastrointestinal fluids collected from treated animals were also measured. Fifteen P. leydeni naturally infected sheep were randomly divided into two groups: untreated control (n = 5) and treated (n = 10). The treated group was orally drenched with OCZ (20 mg/kg, day 0). A second dose was administered 72 h later. Faecal samples were taken at days 0, +3 and +5. Five sheep from both groups were slaughtered at day +5. At necropsies, rumen, abomasum and small intestine were examined for adult and immature flukes. All recovered flukes were counted and the treatment efficacy was estimated. Additionally, serum and gastrointestinal fluid content (ruminal, abomasal and small intestine) samples, obtained from five treated animals at day +5, were analyzed by HPLC to measure OCZ concentrations. OCZ showed high efficacy (99%) against mature P. leydeni. The post-treatment egg reduction was also high after the first dose with values ranging from 98.4% (day +3) to 99.5% (day +5). The highest OCZ concentrations were measured in serum (20.7 ± 11.5 μg/mL) followed by the small intestinal fluid (6.00 ± 4.50 μg/mL). Very low OCZ concentrations (ranging between 0.05 and 0.02 μg/mL) were measured in ruminal and abomasal fluids. OCZ administered to sheep twice (20 mg/kg) by the oral route was highly efficacious against mature stages of P. leydeni in naturally infected sheep. Despite a high drug concentration at the intestinal fluid, OCZ efficacy against immature stages could not be assessed. OCZ efficacy and assessment of its concentration profiles in different tissues are considered a contribution to the scarce information available on this ruminant fluke.
Pharmaceutical treatments of gastrointestinal nematode infections of sheep-Future of anthelmintic drugs
2012, Veterinary Parasitology
Citation Excerpt :
It is therefore important to ensure that these resistant alleles are not afforded any survival advantage as a result of nematode control practices. In practical managemental terms, the selection pressure for anthelmintic resistance is influenced by: the frequency and timing of anthelmintic treatment, the anthelmintic dose rate (Besier and Hopkins, 1988; Martin, 1989; Waller et al., 1996), the anthelmintic drug efficacy (Hennessy, 1993; Hennessy et al., 1994; Sargison et al., 1998) and the proportion of the susceptible population exposed to the anthelmintic compared with that on pasture (Michel, 1985; Van Wyk, 2001). Strategies aimed at reducing the rate of selection for anthelmintic resistance have been widely publicised and are based on these principles (Sargison, 2011).
Various interacting factors have been identified to explain why health plans for nematode parasite control, based on conventional epidemiological knowledge and involving pharmaceutical treatments of their sheep hosts have become unsustainable. Of these, the emergence of anthelmintic resistance has had a major impact on the economics of sheep farming, necessitating fundamental managemental changes. This review focusses on the use of anthelmintic drugs for the control of gastrointestinal nematode infections in sheep, emphasising the need to develop sustainable strategies in the face of inevitable parasite evolution in response to exposure to anthelmintic drugs and other noxious stimuli, or favourable opportunities resulting from changing animal management and climatic factors.
Pharmaceutical Control of Endoparasitic Helminth Infections in Sheep
2011, Veterinary Clinics of North America - Food Animal Practice
Citation Excerpt :
The efficacy of drugs against nematode parasites can be altered by the effects of management on the physiology of their host. The efficacy of benzimidazole and oral macrocyclic lactone anthelmintics is dependent on the duration of nematode exposure to a therapeutic drug concentration, and can be enhanced by prolongation of the drug’s plasma concentration profile.46 Australian studies have shown that this can be achieved by reducing feed intake through yarding for 24 hours before drenching,47 thereby slowing the rate of flow of digesta-bound anthelmintic drug from the rumino-reticulum to the abomasum and site of absorption in the proximal small intestine, and may reduce selection for anthelmintic resistance.48
Uptake of albendazole and albendazole sulphoxide by Haemonchus contortus and Fasciola hepatica in sheep
2000, Veterinary Parasitology
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, 7.5 mg/kg) and the plasma concentrations of ABZSO and ABZ-sulphone (ABZSO₂) 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 (7.5 mg/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 ABZSO₂ 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.
Differences in plasma and abomasal kinetics of albendazole and its metabolites in calves grazed on pasture or fed a grain-based diet
1999, Research in Veterinary Science
We evaluated the comparative plasma and abomasal fluid disposition kinetics of albendazole ( $ABZ$ ) and its metabolites in calves either grazing on pasture or fed a grain-based concentrate diet. Six male Holstein calves (weight 180 to 200 kg) were allowed to graze on lush pasture for three weeks before intraruminal administration of $ABZ$ at 10 mg kg^–1(pasture group). After a three-week wash-out period, the same animals were housed and fed on a grain-based concentrate diet for three weeks prior to receiving the same $ABZ$ treatment (concentrate group). Jugular blood and abomasal fluid samples were collected over 120 hours post-treatment. Plasma and abomasal fluid samples were analysed by high performance liquid chromatography ( $HPLC$ ). The digesta transit time was measured using cobalt (Co) as a fluid marker; abomasal fluid and faecal samples were collected and Co concentrations measured by atomic absorption spectrophotometry. Complementary studies of the in vitro dissolution of $ABZ$ particles at different pH values were also conducted. The pH of abomasal fluid collected from animals kept under both feeding conditions was registered. Increased concentrations of $ABZ$ sulphoxide ( $ABZSO$ ) and sulphone ( $ABZSO$ ₂) in plasma, resulting in significantly higher Cmax and area under the curve ( $AUC$ ) values for both metabolites, were obtained in calves fed on the concentrate diet compared to those grazing on pasture. Enhanced abomasal fluid levels of $ABZ$ and $ABZSO$ were observed in concentrate-fed calves. The mean retention time of the digestive fluid marker in the gastrointestinal (GI) tract was significantly longer in the animals fed the grain-based diet. The in vitro dissolution of $ABZ$ at a pH value equivalent to that obtained in the abomasum of the concentrate-fed calves (1·75) was significantly greater than that obtained at the pH registered in pasture-fed animals (2.00). The characterisation of the kinetic/metabolic behaviours and the resultant efficacy of antiparasitic drugs in animals reared under different management conditions may be relevant in increasing parasite control in livestock.

View all citing articles on Scopus

View full text

The partition and fate of soluble and digesta particulate associated oxfendazole and its metabolites in the gastrointestinal tract of sheep

Abstract

Research in Veterinary Science

International Journal for Parasitology

Research in Veterinary Science

Research in Veterinary Science

International Journal of Applied Radiation and Isotopes

Methyl 5(6)-phenylsulfinyl-2-benzimidazolecarbamate, a new, potent anthelmintic

Journal of Medicinal Chemistry

The rumen as a pharmacokinetic compartment

Estrip, a BASIC computer program for obtaining initial polyexponential parameter estimates

Journal of Pharmaceutical Sciences

Passage of digesta through the intestines of the sheep, retention times in the small and large intestines

British Journal of Nutrition

Analysis of faecal chromium derived from controlled release marker devices

New Zealand Journal of Technology

Fenbendazole: II Biological properties and activity

Pesticide Science

The use of markers to partition digestion within the gastro-intestinal tract of ruminants

Application of the double-marker method for measuring digesta kinetics to rumen sampling in sheep following a dose of the markers or the end of their continuous infusion

Australian Journal of Agricultural Research

Pharmacokinetics

Drugs and the Pharmaceutical Sciences