title: Exploring the potential of flubendazole in filariasis control: evaluation of the systemic exposure for different pharmaceutical preparations.
abstract: The goal of elimination of the human filariases would benefit greatly from the use of a macrofilaricidal agent. In vivo trials in humans and many experimental animal models suggest that flubendazole (FLBZ) is a highly efficacious macrofilaricide. However, since serious injection site reactions were reported in humans after parenteral FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ and its metabolites has acquired urgency in both human and veterinary medicine. The goal of the current work was to compare the systemic exposure of FLBZ formulated as either an aqueous hydroxypropyl-β-cyclodextrin (CD) or aqueous carboxymethyl cellulose (CMC) suspension or a Tween 80-based formulation (TWEEN) in rats and jirds (Meriones unguiculatus). Healthy animals of both species were allocated into four experimental groups of 44 animals each: FLBZ-CD oral and FLBZ-CDsc, treated with the FLBZ-CD formulation by the oral or subcutaneous routes, respectively; FLBZ-TWEENsc, dosed subcutaneously with the FLBZ-TWEEN formulation; and FLBZ-CMC oral, treated orally with the FLBZ suspension. The FLBZ dose was 5 mg/kg. FLBZ and its hydrolyzed (H-FLBZ) and reduced (R-FLBZ) metabolites were recovered in plasma samples collected from rats and jirds treated with the different FLBZ formulations. In both species, FLBZ parent drug was the main analyte recovered in the bloodstream. In rats, FLBZ systemic exposure (AUC 0-LOQ) was significantly (P < 0.05) higher after the FLBZ-CD treatments, both oral (4.8 ± 0.9 µg.h/mL) and subcutaneous (7.3 ± 0.6 µg.h/mL), compared to that observed after oral administration of FLBZ-CMC suspension (0.93 ± 0.2 µg.h/mL). The same differences were observed in jirds. In both species, parenteral administration of FLBZ-TWEEN did not improve the systemic availability of FLBZ compared to FLBZ-CDoral treatment. In conclusion, formulation approaches that enhance the availability of flubendazole in the rat and jird may have therapeutic implications for a drug with poor or erratic bioavailability.
authors.affiliation: Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET, Facultad de Ciencias Veterinarias, UNCPBA, Tandil, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Ceballos
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, School of Veterinary Medicine, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Mackenzie
authors.affiliation: Institute of Parasitology, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Geary
authors.affiliation: Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET, Facultad de Ciencias Veterinarias, UNCPBA, Tandil, Argentina.
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez
authors.affiliation: Laboratorio de Farmacología, Centro de Investigación Veterinaria de Tandil (CIVETAN), CONICET, Facultad de Ciencias Veterinarias, UNCPBA, Tandil, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lanusse
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000969:Antinematodal Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D005849:Gerbillinae; D008463:Mebendazole / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D000969:Antinematodal Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D008463:Mebendazole; D002266:Carboxymethylcellulose Sodium; C018945:flubendazole