P-glycoprotein interfering agents potentiate ivermectin susceptibility in ivermectin sensitive and resistant isolates of Teladorsagia circumcincta and Haemonchus contortus
Résumé
P-glycoprotein (P-gp) homologues, belonging to the ATP Binding Cassette (ABC) transporter family, are thought to play an important role in the resistance of gastro-intestinal nematode parasites against macrocyclic lactones. The aim of this study was to investigate the influence of various P-gp interfering compounds on the efficacy of ivermectin (IVM) in sensitive and resistant nematode isolates. The feeding of IVM resistant and sensitive Teladorsagia circumcincta and Haemonchus contortus first-stage larvae (L1) was assessed using a range of IVM concentrations (0.08-40 nm) with or without P-gp inhibitors: valspodar, verapamil, quercetin, ketoconazole and pluronic P85. The P-gp inhibitors were selected on the basis of their ability to interfere with P-gp transport activity in an epithelial cell line over-expressing murine P-gp. In the presence of P-gp interfering agents, the in vitro susceptibility to IVM of both sensitive and resistant isolates of T. circumcincta and H. contortus was increased. These results show that compounds interfering with P-gp transport activity could enhance IVM efficacy in sensitive isolates, and also restore IVM sensitivity in resistant nematodes. These results support the view that ABC transporters can play an important role in resistance to IVM, at least in the free-living stages of these economically important gastro-intestinal nematodes.