Abstract
BackgroundFlubendazole (FLBZ) is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound. Cyclodextrins (CDs) are usually used to increase aqueous solubility of poor hydrosoluble compounds. The comparative in vitro aqueous solubility of FLBZ and other BZD anthelmintics in the presence of hydroxypropyl-β-cyclodextrin (HPβCD) was evaluated in the current work. Additionally, the comparative pharmacokinetic behaviour of FLBZ (and its metabolites) administered by the intraruminal (i.r.) or intraabomasal (i.a.) routes to sheep as either an aqueous CDs-based solution or a conventional carboximethylcellulose (CMC) suspension was assessed. Drug solubility studies involving albendazole, mebendazole, oxfendazole and FLBZ were performed in an aqueous solution (pH 1.2 or 7.4) with or without HPβCD (10%, w/v). The pharmacokinetic study involved two experiments. Experiment 1: In a crossover study, sheep received either a FLBZ-CDs solution (n = 3) or a FLBZ-CMC suspension (n = 3) by the i.r. route (3.8 mg/kg). The treatment Groups were reversed after a 21-days washout period. Experiment 2: sheep (n = 4) were treated by the i.a. route with the FLBZ-CDs solution (3.8 mg/kg). Plasma and abomasal fluid samples were collected between 0 and 72 h post-treatment. Samples were analysed by HPLC.ResultsImprovement of FLBZ aqueous solubility due to CDs resulted markedly higher than that observed for mebendazole and albendazole. However, oppositely to what was expected, the absorption-related pharmacokinetic parameters did not show any marked formulation-dependant effect. After the i.a. administration of FLBZ, the AUC and the Tmax of the parent compound were significantly (P < 0.05) reduced, which is consistent with ruminal bypass.ConclusionThe administration of FLBZ as a CDs-based solution, does not seem to achieve great practical relevance for parasite control in sheep.
Highlights
Flubendazole (FLBZ) is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound
The antiparasitic activity of BZD anthelmintics largely depends on their affinity for parasite ß-tubulin, the putative mode of action [5], and on their ability to reach high and sustained concentrations at the site of parasite location; which, in turn, depends on pharmacokinetic, metabolic and tissue distribution processes in the host [6]
BZD solubility greatly increased at a pH value of 1.2, in which the highest aqueous solubility (6.6 ± 1.3 mg/mL) was observed for the most polar albendazole sulphoxide (ABZSO) metabolite
Summary
Flubendazole (FLBZ) is a poor water solubility broad-spectrum BZD methylcarbamate anthelmintic compound. The comparative pharmacokinetic behaviour of FLBZ (and its metabolites) administered by the intraruminal (i.r.) or intraabomasal (i.a.) routes to sheep as either an aqueous CDs-based solution or a conventional carboximethylcellulose (CMC) suspension was assessed. Plasma and abomasal fluid samples were collected between 0 and 72 h post-treatment. Flubendazole (FLBZ) is a broad-spectrum benzimidazole (BZD) methylcarbamate anthelmintic available for use in human and some domestic animals. It is widely used for parasite control in pigs, chicken, turkeys and game birds. Because the low aqueous solubility of the methylcarbamate BZD compounds, poor/erratic gastrointestinal absorption is a common inconvenient for the systemic availability of orally administered BZD in most species [6]. Enhanced systemic availability of the parent drug/active metabolite obtained by increased drug absorption will correlate with an improved antiparasitic effect
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