Integrated pharmacological assessment of flubendazole potential for use in sheep: disposition kinetics, liver metabolism and parasite diffusion ability¹

Abstract

Flubendazole (FLBZ) is a broad spectrum benzimidazole methylcarbamate anthelmintic widely used in poultry and swine. However, there is no information available on the pharmacological behaviour of FLBZ in ruminants. The work reported here was addressed to evaluate the potential of FLBZ for use in sheep. The integrated assessment included evaluation of FLBZ and metabolites plasma disposition kinetics, liver metabolism and ex vivo ability to diffuse into the cestode parasite Moniezia benedeni. In a cross-over kinetic study, six healthy Corriedale sheep were treated with FLBZ by intravenous (i.v.) (4% solution) and intraruminal (i.r.) (4% suspension) administrations at the same dosage (5 mg/kg) with a 21-day washout period between treatments. Blood samples were collected between 0 and 72 h post-treatments. Sheep liver microsomes were incubated with 40 microm FLBZ and specimens of the cestode parasite M. benedeni, collected from untreated animals, were incubated (5-120 min) with FLBZ and its reduced (R-FLBZ) metabolite (5 microm). Samples of plasma, microsomal incubations and parasite material were prepared and analyzed by high-performance liquid chromatography to measure FLBZ and its metabolites. FLBZ parent drug showed a fast disposition being detected in the bloodstream up to 36 h after its i.v. administration. Both R-FLBZ and hydrolyzed FLBZ (H-FLBZ) metabolites were recovered in plasma as early as 5 min after the i.v. treatment in sheep. The plasma AUC ratios for R-FLBZ and FLBZ (AUC(R-FLBZ)/AUC(FLBZ)) were 4.07 i.v. and 5.55 i.r., respectively. R-FLBZ achieved a significantly higher (P < 0.01) C(max) value (0.14 microg/mL at 17.3 h post-treatment) than that observed for the parent drug FLBZ (0.04 microg/mL at 14.4 h post-treatment). Low plasma concentrations of FLBZ parent drug were measured between 6 and 48 h, and only trace concentrations of H-FLBZ were detected during a short period of time after the i.r. treatment. Consistently, sheep liver microsomes metabolized FLBZ into its reduced metabolite at a rate of 9.46 +/- 2.72 nmol/mg/h. Both FLBZ and R-FLBZ demonstrated a similar ability to quickly diffuse through the tegument of the cestode parasite. The data on FLBZ pharmacological behaviour presented here contribute to evaluate its potential to be developed as an anthelmintic for broad spectrum parasite control in ruminants.

Comparative Performances of Flubendazole and Albendazole in Cystic Echinococcosis: Ex Vivo Activity, Plasma/Cyst Disposition, and Efficacy in Infected Mice

“…The main metabolic pathways for FLBZ include reduction to form reduced FLBZ (R-FLBZ) and hydrolysis of the methylcarbamate group to form the hydrolyzed-FLBZ metabolite (H-FLBZ). R-FLBZ was the main analyte recovered from the bloodstream of sheep (25) and mice (8) treated with FLBZ, in which only trace amounts of H-FLBZ were detected. Likewise, while H-FLBZ is an inactive metabolite, some biological activity has been described for R-FLBZ (1).…”

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

“…Reduction of the carbonyl group (reduced flubendazole, FLUR) and carbamate hydrolysis (hydrolyzed flubendazole, FLUH) were the major biotransformation reactions [14,20,33].…”

“…Until now, FLU has been prescribed only for swine and poultry, but the extension of its usage to small ruminants [31,33] (in oral suspension or with food as a premix) could be beneficial because of the broad spectrum of its anthelmintic activity. Additionally, FLU has a different biotransformation pattern in the host than other benzimidazoles due to the presence of carbonyl groups and absence of sulfur atoms in its molecule.…”

“…Albendazole, fenbendazole and oxfendazole are the most widely used benzimidazoles in ruminant species. While sulfoxide metabolites are the main analytes detected in the bloodstream after the intraruminal administration of albendazole and fenbendazole [28,29], the reduced FLU was generally the main molecule recovered in the systemic circulation of FLU-treated sheep [24,33]. Higher concentrations of the lipophilic thioethers albendazole and fenbendazole were detected in Moniezia benedeni after ex vivo incubation, compared to their more polar sulfoxide metabolites [34].…”

“…Higher concentrations of the lipophilic thioethers albendazole and fenbendazole were detected in Moniezia benedeni after ex vivo incubation, compared to their more polar sulfoxide metabolites [34]. A similar pattern of diffusion to the cestode parasite was observed for both FLU and reduced FLU, which probably indicates the similar lipid solubility of both albendazole and fenbendazole [33]. In experimental studies, FLU was used successfully in the therapeutic treatment of mouflon muelleriosis [26,27].…”