Exploring flubendazole formulations for use in sheep. Pharmacokinetic evaluation of a cyclodextrin-based solution

Improvement 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.The administration of FLBZ as a CDs-based solution, does not seem to achieve great practical relevance for parasite control in sheep.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. FLBZ is commercially available for oral administration as a paste, tablets, pellet or premix formulations [1]. BZD anthelmintics are extensively biotransformed in all mammalian species studied [2]. FLBZ is metabolized by microsomal and cytosolic fractions obtained from sheep liver and duodenal mucosa into a reduced FLBZ metabolite (R-FLBZ) [3]. R-FLBZ was the main analyte recovered from the bloodstream of FLBZ treated sheep [4], in which only trace amounts of the hydrolysed metabolite (H-FLBZ) were detected.The antiparasitic activity of BZD anthelmintics largely depends on their affinity for parasite ？-tubulin, the putative mode of action [5], but also 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]. Despite the type of helminth involved, the higher the concentrations achieved at the parasite location, the higher the amount of drug reaching the target parasite [7], which is strongly supported by the findings from different in vivo studies [8-10] where systemic drug availability and efficacy were simultaneously estimated. Because the low aqueo