title: Dose-dependent systemic exposure of albendazole metabolites in lambs.
abstract: The gastrointestinal absorption of most drugs follows a first-order kinetics, whereby a constant fraction of the total drug is absorbed in each equal time interval. Although this related absorption principle is applicable to the most of the therapeutically used drugs, it remains unclear for poorly water-soluble compounds such as the benzimidazole anthelmintics in ruminants. The goal of the current work was to characterize the albendazole (ABZ) metabolites plasma disposition kinetics after ABZ administration at different dosages to nematode-infected lambs. Eighteen Corriedale lambs artificially infected with a resistant Haemonchus contortus strain were allocated into three groups and intraruminally treated with ABZ at either 5 (ABZ(5)), 15 (ABZ(15)) or 45 (ABZ(45)) mg/kg. Blood samples were collected up to 120 h post-treatment, and the collected plasma was analysed by high-performance liquid chromatography. The estimated pharmacokinetic parameters were statistically compared using parametric and nonparametric tests. None of the animals involved in the current trial showed any adverse events during the study. While ABZ parent drug was not recovered in the bloodstream, the area under the concentration vs time curve (AUC) of the active ABZ-sulphoxide (ABZSO) metabolite increased significantly (P<0.05) from 21.0 (ABZ(5)) up to 158.6 (ABZ(15)) and 389.7 μg·h/mL (ABZ(45)), which indicates some type of nonproportionality in the relationship between dose level and drug systemic exposure. The overall kinetic disposition of the inactive sulphone metabolite did not change after treatment at threefold the therapeutic ABZ dosage. However, significantly (P<0.05) higher AUC, C(max) and mean residence time values were observed after the administration of the highest dosage level. The higher dosages accounted for a significantly (P<0.05) enhancement of the ABZSO peak plasma concentration, which were obtained at delayed times post-treatment. High correlations between AUC(0-LOQ) and C(max) and nematode counts were observed, with Spearman's coefficients of -0.83 and -0.84, respectively. The results obtained in the current experiment show that increasing the dose of ABZ in sheep is clearly associated with enhanced plasma ABZ metabolites exposure. The data showed a nonproportionality on the gastrointestinal absorption of ABZ in nematode-infected lambs.
authors.affiliation: Laboratorio de Farmacología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA), Campus Universitario, Tandil, Argentina. lalvarez@vet.unicen.edu.ar
authors.forename: L
authors.initials: L
authors.lastname: Alvarez
authors.forename: G
authors.initials: G
authors.lastname: Suárez
authors.forename: L
authors.initials: L
authors.lastname: Ceballos
authors.forename: L
authors.initials: L
authors.lastname: Moreno
authors.forename: C
authors.initials: C
authors.lastname: Lanusse
mesh_terms: D015766:Albendazole / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000871:Anthelmintics / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D019540:Area Under Curve; D041981:Gastrointestinal Tract / Q000378:metabolism; D006207:Half-Life; D012756:Sheep / Q000097:blood*
chemical_list: D000871:Anthelmintics; D015766:Albendazole; C027186:albendazole sulfoxide