Pharmacological strategies to improve ivermectin efficacy against resistant nematodes

Abstract

The involvement of the efflux-transport protein P-glycoprotein (Gp-P) on both the pharmacokinetic disposition and resistance mechanisms to macrocyclic lactones has been described. This work aimed to study the effects of loperamide (LPM), a Gp-P modulating agent, on ivermectin (IVM) pharmacokinetics and efficacy against resistant nematodes in sheep. Eighteen Corriedale lambs naturally infested with gastrointestinal nematodes were assigned into three experimental groups. Group A remained as untreated control. Other animals (Groups B and C) received ivermectin either alone or co-administered with LPM (0.2 mg/kg, 2 times every 12 h). Blood samples were collected between up to 14 days post-treatment and IVM plasma concentrations were determined by HPLC. The pattern of efficacy was estimated by the faecal egg count reduction test (FECRT) and adult nematode counts. LPM enhanced the IVM plasma availability (47 %) in co-administered lambs. The FECRT values were increased from 79 % to 96 % in the presence of LPM. The general efficacy against nematodes was increased from 48 % to 77 % after the LPM co-administration. The clinical relevance of this pharmacokinetic/pharmacodynamic interaction is under study in our laboratory.