RESUMO
The current experiments compare the pattern of ex vivo uptake (diffusion) of albendazole (ABZ) and albendazole sulfoxide (ABZSO) by Ascaris suum and Fasciola hepatica. Specimens of A. suum and F. hepatica were collected from untreated animals (pigs and sheep, respectively) and incubated with either ABZ or ABZSO for different time periods (5-180 min). After incubation. the parasite material was analysed by HPLC to quantify the amount of ABZ and/or ABZSO. The parent drug and its active ABZSO metabolite were recovered from the parasites after ex vivo incubation for different time periods throughout the assay. Total drug availability in A. suum, expressed as area under the concentration versus time curve (AUC) over 180 min of incubation, was significantly greater (P<0.05) for ABZ parent drug (AUC = 4.19 +/- 0.59 microg x h xg(-1)) compared with the more polar ABZSO metabolite (AUC = 0.25 +/- 0.01 micro x h x g(-1)). Similar results were observed after the incubation of both molecules with F. hepatica, where the AUC values obtained were 10.6 +/- 0.28 microg x h x g(-1) and 2.04 +/- 0.33 microg x h x g(-1) for ABZ and ABZSO, respectively. The greater diffusion and availability of ABZ in both helminths correlate with the higher lipophilicity of the parent drug, compared with its sulfoxide metabolite. The amount of both molecules measured in A. suum was significantly lower (P<0.05) than that recovered in F. hepatica. The complexity of the histological structure of the nematode cuticle compared with the external tegument of the trematode may account for such a difference in drug diffusion between the species. These findings complement previous observations on the patterns of in vivo uptake of ABZ by different helminth parasites, contributing to the understanding of the pharmacological anthelmintic action of these moieties.
Assuntos
Albendazol/análogos & derivados , Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Ascaris suum/metabolismo , Fasciola hepatica/metabolismo , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Ovinos , SuínosRESUMO
The pattern of in vivo uptake of albendazole (ABZ) and its major metabolite, ABZ-sulphoxide (ABZSO), by Haemonchus contortus and Fasciola hepatica recovered from ABZ-treated sheep, was investigated. Concentration profiles of both compounds were simultaneously measured in target tissues/fluids from the same infected sheep. In addition, the proportion of the (+) and (-) ABZSO enantiomers was determined in plasma, bile and F. hepatica recovered from treated sheep. Sheep naturally infected with H. contortus were intraruminally (i.r.) treated with ABZ (micronized suspension, 7. 5mg/kg) and the plasma concentrations of ABZSO and ABZ-sulphone (ABZSO(2)) determined in addition to the concentration of ABZ and ABZSO in H. contortus, abomasal mucosa and fluid content samples. In addition, F. hepatica artificially infected sheep were treated i.r. with the same ABZ suspension (7.5mg/kg), and samples of blood, bile, liver tissue and adult flukes were collected and analysed by HPLC to determine the concentrations of ABZ and both enantiomers of ABZSO. ABZSO and ABZSO(2) were the analytes recovered in plasma with ABZ and ABZSO present in H. contortus. ABZ was the analyte recovered at the highest concentration in H. contortus and abomasal mucosa, whereas higher concentrations of ABZSO were measured in abomasal fluid content. Only low concentrations of ABZ were detected in F. hepatica and bile, but markedly higher concentrations of ABZ were measured in liver tissue. ABZSO was the main molecule recovered in F. hepatica, plasma and bile samples collected from ABZ-treated sheep. The (+) enantiomer of ABZSO was recovered at a higher proportion in plasma (75%), bile (78%) and F. hepatica (74%) after ABZ administration to infected sheep.
Assuntos
Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Fasciola hepatica/metabolismo , Fasciolíase/veterinária , Hemoncose/veterinária , Haemonchus/metabolismo , Doenças dos Ovinos/parasitologia , Abomaso/parasitologia , Albendazol/administração & dosagem , Albendazol/análise , Albendazol/uso terapêutico , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/análise , Anti-Helmínticos/uso terapêutico , Proteínas Sanguíneas/análise , Cromatografia Líquida de Alta Pressão/veterinária , Fasciola hepatica/crescimento & desenvolvimento , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Glutamato Desidrogenase/sangue , Hemoncose/tratamento farmacológico , Hemoncose/parasitologia , Haemonchus/crescimento & desenvolvimento , Masculino , Albumina Sérica/análise , Soroglobulinas/análise , Ovinos , Doenças dos Ovinos/sangue , Doenças dos Ovinos/tratamento farmacológico , Estereoisomerismo , gama-Glutamiltransferase/sangueRESUMO
The current experiments correlate the disposition kinetics of albendazole (ABZ) following its intravenous (i.v.) and intraruminal (i.r.) administrations to Moniezia spp.-infected sheep, with the pattern of drug/metabolite uptake by tapeworms collected from treated animals. The ex vivo uptake pattern of ABZ and albendazole sulphoxide (ABZSO) by the same cestode parasite was also investigated. Naturally infected (Moniezia spp.) Corriedale lambs were treated with ABZ by either i.v. (Group A, n = 15) or i.r. (Group B, n = 15) administration at 7.5 mg/kg. Plasma and abomasal fluid samples were obtained over a 120-h period. Two animals per group were killed at 0.5, 1, 2, 4 and 6 h post-treatment; parasite material (tapeworms), bile and intestinal fluid samples were recovered. Furthermore, Moniezia spp. tapeworms obtained from sheep killed at the local abattoir were incubated with either ABZ or ABZSO for different time periods in a Kreb's Ringer Tris buffer (ex vivo experiments). Samples were analysed by high performance liquid chromatography for ABZ, ABZSO and albendazole sulphone (ABZSO2). ABZ plasma concentrations decreased rapidly and were not detectable beyond 10 h following i.v. administration. ABZSO and ABZSO2 were the metabolites recovered in plasma after both treatments. ABZ and its metabolites were extensively distributed to the digestive tract, mainly into the abomasal fluid, after the i.v. and i.r. administrations. The parent drug and its active ABZSO metabolite were recovered in tapeworms collected from both i.v. and i.r. treated lambs. However, the availability of both ABZ and ABZSO was higher in parasite material recovered from i.v. treated animals. The uptake of ABZ by the cestode parasite, both in vivo and ex vivo, was significantly greater than that of its sulphoxide metabolite, which agrees with the higher lipophilicity of the parent drug.
Assuntos
Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Cestoides/metabolismo , Ovinos/metabolismo , Ovinos/parasitologia , Abomaso/metabolismo , Albendazol/administração & dosagem , Albendazol/sangue , Algoritmos , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/sangue , Área Sob a Curva , Biotransformação , Injeções Intravenosas , Masculino , Sulfóxidos/metabolismo , Distribuição TecidualRESUMO
The plasma and abomasal fluid disposition kinetics of ricobendazole (RBZ) after subcutaneous (s.c.) administration of a novel injectable formulation to calves, and the comparative plasma availability after s.c. injection of RBZ and that obtained after oral treatment with albendazole (ABZ), were characterised. Six parasite-free Holstein calves received RBZ (solution 150 mg ml(-1)) by s.c. injection at 3.75 mg kg(-1) (Experiment 1). Experiment 2 was conducted in two experimental phases; in phase I, five calves (Group A) received RBZ by s.c. injection and five animals (Group B) were orally treated with ABZ (suspension 100 mg ml(-1)), at 5 mg kg(-1). Drug treatments were reversed for each group in phase II and given at 7.5 mg kg(-1). Samples of abomasal fluid (via cannula) and jugular blood were collected over 72 hours post-treatment and analysed by HPLC. RBZ and its sulphone metabolite were detected in plasma following its s.c. administration. RBZ was rapidly absorbed, reaching the plasma Cmax at 4.5 hours post-dosing. The sulphone metabolite followed a similar kinetic pattern. Both molecules were rapidly and extensively distributed into the abomasum, being detected in abomasal fluid between 30 minutes and 36 hours post-administration. An extensive plasma/abomasum exchange process, with ionic-trapping in the abomasum, accounted for the higher AUC value (>200 per cent) obtained for RBZ in abomasum compared with plasma. The s.c. treatment with RBZ formulated as a solution resulted in a significantly greater plasma availability (measured as ABZ sulphoxide) than the oral treatment with ABZ (suspension) given at the same dose rates.
Assuntos
Albendazol/análogos & derivados , Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Bovinos/metabolismo , Administração Oral , Albendazol/administração & dosagem , Albendazol/metabolismo , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/metabolismo , Área Sob a Curva , Disponibilidade Biológica , Bovinos/sangue , Cromatografia Líquida de Alta Pressão , Meia-Vida , Injeções SubcutâneasRESUMO
The influence of gastrointestinal nematode infection on the kinetics of albendazole (ABZ) and its metabolites, albendazole sulphoxide (ABZSO) and sulphone (ABZSO2) in plasma and abomasal fluid was investigated in sheep. A micronised suspension of ABZ was administered intraruminally at 7.5 mg kg-1 to the following groups of sheep: (a) non-parasitised (control); (b) artificially infected with Haemonchus contortus; (c) naturally infected with Haemonchus contortus and other species of gastrointestinal nematodes. Plasma and abomasal fluid samples were obtained serially over 72 h post-treatment and they were analysed by HPLC for ABZ and its metabolites. The ABZ parent drug was not detected in plasma at any time post-treatment, however the metabolites ABZSO and ABZSO2 were recovered in the bloodstream. The active metabolite ABZSO was recovered in plasma between 0.5 and 48 (uninfected), 60 (H. contortus infected) or 72 h (naturally infected sheep) post-administration. The area under the plasma concentration vs time curve (AUC) values for ABZSO were higher in both artificially infected (64.0 micrograms h ml-1) and naturally infected (79.3 micrograms h ml-1) sheep as compared with non-infected animals (41.8 micrograms h ml-1). Peak plasma concentrations for ABZSO and ABZSO2 were higher in both artificially and naturally infected sheep than in non-parasitised animals. No changes in the half-lives and mean residence times for these metabolites were observed in infected sheep. ABZ and its metabolites were found in the abomasum between 0.5 and 48 (infected animals) or 72 h (uninfected) post-treatment. The availability (total AUCs) of ABZ and its metabolites in abomasal fluid were lower in H. contortus infected sheep than in the uninfected control animals. The increased abomasal pH induced by the presence of the H. contortus infection may reduce the plasma/abomasum pH gradient, which results in a decreased ionic-trapping of ABZ and its metabolites in the abomasum. Such a phenomenon correlates with: (a) the higher total AUC values obtained for ABZ metabolites in the bloodstream of the infected compared to the control sheep, (b) the lower concentration profiles of the ABZ parent drug and its metabolites found in the abomasal fluid of the infected animals.
Assuntos
Abomaso/metabolismo , Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Hemoncose/veterinária , Doenças dos Ovinos/metabolismo , Albendazol/análogos & derivados , Albendazol/sangue , Albendazol/metabolismo , Animais , Anti-Helmínticos/metabolismo , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Hemoncose/sangue , Hemoncose/metabolismo , Meia-Vida , Masculino , Ovinos , Doenças dos Ovinos/sangueRESUMO
The influence of fasting on the bioavailability and disposition kinetics of albendazole (ABZ) and its metabolites in cattle was investigated. ABZ (10 mg/ kg) was given by intraruminal (i.r.) (Experiment 1) and intravenous (i.v.) (Experiment 2) administration to Holstein calves either fed ad libitum (control) or subjected to a 48 h fasting period (fasted group) prior to treatment. The rate of passage of digesta through the gastrointestinal (GI) tract was evaluated by measurement of cobalt faecal excretion following the oral administration of the sodium-cobalt-ethylendiamine-tetracetic acid complex to calves subjected to the feeding conditions above described. Jugular blood and abomasal fluid (via cannula) samples were collected over 120 h post-treatment; samples were analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2). Fasting the animals prior to the i.r. treatment resulted in pronounced modifications to the plasma and abomasal fluid disposition kinetics of ABZ and its metabolites. A greater extent of GI absorption with significantly higher CmaX (150%) and AUC (310%) values for ABZSO in plasma, was observed in fasted compared to fed animals following the i.r. administration of ABZ. Extended detection of ABZ metabolites resulting in significantly longer plasma t 1/2el and MRT was also obtained in fasted compared to fed calves. These results correlated with the substantially enhanced availability of ABZ and its metabolites (AUCs over 200% greater) in the abomasal fluid of the fasted animals. Fasting did not induce changes to the plasma disposition of either ABZ or its metabolites after the i.v. treatment. The digesta passage rate, measured by the amount of cobalt excreted in faeces, was significantly lower in fasted compared to animals fed ad libitum. A delayed GI transit time that decreases the rate of passage of the drug down the digestive tract, may have accounted for enhanced ABZ dissolution and absorption in fasted compared to fed calves. The findings reported in this article show that fasting prior to treatment notably affects the bioavailability and disposition kinetics of ABZ and its metabolites in cattle.
Assuntos
Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Bovinos/metabolismo , Jejum/metabolismo , Abomaso/metabolismo , Administração Oral , Albendazol/administração & dosagem , Albendazol/farmacologia , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Disponibilidade Biológica , Biotransformação , Cromatografia Líquida de Alta Pressão/veterinária , Cobalto/metabolismo , Fezes/química , Trânsito Gastrointestinal/efeitos dos fármacos , Injeções Intravenosas/veterinária , Veias Jugulares , Masculino , Rúmen/metabolismoRESUMO
The influence of diet on the disposition kinetics of albendazole (ABZ) and its metabolites in pigs was investigated. ABZ was administered orally at 10 mg kg-1 to pigs fed either a commercially produced 35 per cent protein/grain concentrate diet (concentrate group), a whey-based diet supplemented with corn grain (whey/grain group) or grazed on pasture (pasture group). Blood samples were taken serially for 96 hours and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO), ABZ sulphone (ABZSO2) and amino-ABZSO2 (NH2ABZSO2). ABZ was not detected in plasma at any time after the treatment, and ABZSO and ABZSO2 were the main metabolites detected between 0.5 and 30 to 48 hours after treatment in all the experimental animals. Low concentrations of the NH2ABZSO2 metabolite were found in plasma between 18 and 36 hours after the administration of ABZ to all the groups of pigs. The pharmacokinetic behaviour of the ABZ metabolites in pigs fed either the concentrate of the whey/concentrate diet was substantially different from that observed in pigs grazing on pasture. The peak concentration (C(max)) and areas under the concentration-time curves (AUC) for ABZSO and ABZSO2 were significantly higher (P < 0.01) in the pigs fed on pasture, and were correlated with significantly longer elimination half-lives and mean residence times for both metabolites.
Assuntos
Albendazol/análogos & derivados , Albendazol/farmacocinética , Anti-Helmínticos/farmacocinética , Dieta , Albendazol/sangue , Albendazol/metabolismo , Animais , Anti-Helmínticos/metabolismo , Cromatografia Líquida de Alta Pressão , Proteínas Alimentares , Feminino , Alimentos Fortificados , Masculino , Proteínas do Leite , Poaceae , Suínos , Fatores de Tempo , Proteínas do Soro do LeiteRESUMO
1. The influence of nutritional status on the plasma and abomasal fluid disposition kinetics of albendazole (ABZ) and its metabolites, albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2), has been investigated in the calf. 2. Free fatty acid (FFA) and beta-hydroxybutyrate (beta-OHB) serum concentrations were significantly higher in the feed-restricted (poor nutritional status) compared with control calf (optimal nutritional status). 3. ABZ parent drug was not detected in plasma at any time post-treatment and ABZSO and ABZSO2 were the metabolites detected in plasma. Both metabolites were rapidly depleted from the bloodstream. ABZ and its metabolites were recovered in abomasal fluid from 0.25 up to either 48 (ABZ) or 120h (ABZSO and ABZSO2) post-treatment. 4. The plasma disposition kinetics of both ABZ metabolites was significantly changed in the feed-restricted compared with control calf. ABZSO and ABZSO2 plasma area under the curves (AUCs) were significantly higher in the restricted animal. These enhanced AUCs correlated with significantly longer plasma half-lives (T1/2el) and mean residence times (MRTs) for these metabolites. 5. The delayed elimination of ABZ metabolites from the bloodstream correlated with the higher concentration of these molecules recovered in the abomasal fluid of the calves subjected to a dietary restriction. 6. The changes observed on disposition kinetics may reflect an impairment on the hepatic metabolism and clearance of ABZ as a consequence of FFA mobilization from adipose tissue and overproduction of ketone bodies in the liver.