Modulation of drug cellular efflux improves ivermectin activity against resistant nematodes. Integrated pharmaco-parasitological assessment.

LIFSCHITZ, A.; ENTROCASSO, C.; ALVAREZ, L.; LLOBERAS, M.; BALLENT, M.; MANAZZA, G.; VIRKEL, G.; BORDA, B.; LANUSSE, C.

Calgary, Canada

Conferencia; 22 International Conference of the World Association for the Advancement of Veterinary Parasitology; 2009

Asociacion Mundial para el avance de la Parasitología Veterinaria

The involvement of P-glycoprotein (P-gp) on IVM disposition kinetics has been demonstrated. P-gp over expression accounts for enhanced drug efflux in IVM resistant nematodes. The aim of this trial was to assess the effects of loperamide (LPM), a P-gp modulating agent, on IVM pharmacokinetics and efficacy against resistant nematodes in lambs. Eighteen (18) Corriedale lambs naturally infected with gastrointestinal nematodes were allocated into three (3) experimental groups. Group A remained as untreated control. Animals in Groups B and C received IVM (subcutaneously, 0.2 mg/kg) either alone or co-administered with LPM (0.2 mg/kg, twice every 12 h). Blood samples were collected between 0 and 14 days post-treatment and IVM plasma concentrations were determined by HPLC (Pharmacokinetic trial). LPM enhanced the IVM plasma availability (P<0.05) and prolonged its elimination half-life (P<0.05) in co-administered lambs.  Faecal individual samples were collected from animals at days -1 and 14 post-treatment to perform the faecal eggs count reduction test (FECRT). Additionally, at day 14 post-treatment, animals were sacrificed and adult gastrointestinal nematode counts were performed (Efficacy trial)..As earlier shown in cattle, the FECRT values increased from 79 % to 96 % after LPM coadministration. The efficacy against Trichostrongylus colubriformis increased from 77.9 % (IVM alone) to 96.3 % (IVM+LPM). A similar trend was observed for Nematodirus spp.  LPM modulates the P-gp–mediated intestinal and hepatic excretion of IVM in the host, and it may also interact with the P-gp efflux transport over expressed in resistant nematodes, which would account to increase worm exposure to IVM.