Evaluation of the effect of increasing albendazole dose rates against resistant Haemonchus contortus: Drug systemic availability, clinical efficacy and genetic polymorphism.

ALVAREZ, L; VIRGINIE BARRERE, V; SUAREZ, G; CEBALLOS, L; MORENO, L; PRICHARD, R; LANUSSE, C

Congreso; 22sh International Conference of the World Association for the Advancement of Veterinary Parasitology; 2011

The gastrointestinal absorption of most drugs follows a first-order kinetics, whereby a constant fraction of the total drug is absorbed in each equal interval of time. This is applicable to the most of the therapeutically used drugs, but remains unclear for the poorly water soluble benzimidazole (BZD) anthelmintics in ruminants. The main goals of the current trial were: a) to characterize the albendazole (ABZ) metabolites plasma disposition kinetics after ABZ administration at different dose rates to lambs, b) to compare the clinical efficacy of different ABZ dose levels in lambs infected with a BZD-resistant strain of Haemonchus contortus, and c) to analyze the frequency of mutations at three different single nucleotide polymorphisms (SNP) on the beta-tubulin isotype 1 encoding gene in worms surviving the treatments at different dosages. Twenty four (24) Corriedale lambs artificially infected with a resistant H. contortus strain were allocated into 4 groups (n=6) and intraruminally treated with ABZ at either 5 (ABZ5), 15 (ABZ15) or 45 (ABZ45) mg/kg.  Plasma samples were collected up to 120 h post-treatment and analyzed by HPLC. An untreated control Group was included to assess the comparative anthelmintic efficacy of the different treatments against H. contortus. Additionally, adult specimens of H. contortus were recovered directly from the abomasum for genetic analysis. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). The area under the concentration vs time curve (AUC) of the active ABZ-sulphoxide metabolite increased from 21  (ABZ5) up to 159 (ABZ15) and 390 µg.h/mL (ABZ45),which indicates some type of non-linearity in the relationship between dose level and systemic drug availability. The efficacies against resistant H. contortus were 20% (ABZ5) 74% (ABZ15) and 98% (ABZ45). The enhanced systemic exposure achieved after treatments at the highest dose rates correlated with significant increment in drug efficacy against a resistant H. contortus strain. There was a strong relationship between the increase in drug selection pressure (treatments at the highest dosages) and a particular association between SNP200 and SNP167 in the population tested. The association Phe/Phe167 – Tyr/Tyr200 conferred high levels of resistance