Modulation of P-glycoprotein enhances ivermectin and moxidectin systemic availabilities and their efficacy against resistant nematodes in cattle

LIFSCHITZ, A.; SALLOVITZ, J.; IMPERIALE, F.; SUAREZ, V.; CRISTEL, S.; AHOUSSOU, S.; LANUSSE, C.

Gent, Belgica

Congreso; 21st International Conference of the World Association for the Advancement of Veterinary Parasitology (WAAVP); 2007

World Association for the Advancement of Veterinary Parasitology (WAAVP)

The involvement of the efflux-transport protein P-glycoprotein on both the pharmacokinetic disposition and resistance mechanisms to macrocyclic lactones has been described. This work aimed study the effects of loperamide, a P-glycoprotein modulating agent, on ivermectin and moxidectin pharmacokinetics and efficacy against resistant nematodes in cattle. Fifty Aberdeen Angus male calves (180-200 kg) were assigned into five experimental groups. Group A remained as untreated control. Other animals received ivermectin (Group B) or moxidectin (Group C) (200 mg/kg, subcutaneously) either alone or co-administered with loperamide (0.4 mg/kg, 3 times every 24h) (Groups D and E). Blood samples were collected between up to 30 days post-treatment and drug plasma concentrations were determined by HPLC with fluorescence detection. The pattern of efficacy was estimated by faecal egg count reduction test (FECRT). Nematode larvae were identified by 4 pooled faecal cultures for each group. Cooperia spp. and Ostertagia spp. were the predominant nematode larvae in pre-treatment cultures. The FECRT values confirm the presence of resistant nematode populations (largely Cooperia spp.) to both ivermectin (23%) and moxidectin (69%). Loperamide enhanced the plasma concentrations of ivermectin and moxidectin in co-administered calves. This loperamide-induced pharmacokinetic modification accounted for enhanced egg counts reduction for both ivermectin (50%) and moxidectin (87%). The in vivo modulation of the P-glycoprotein-mediated drug efflux increased drug systemic availability and efficacy against resistant nematodes. Further work to evaluate the clinical relevance of this pharmacokinetic/pharmacodynamic interaction is undergoing in our laboratory.