An Investigation of the Mechanism of Ivermectin Resistance in the Nematode Parasite, Haemonchus contortus
Musser, Sara E.
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Haemonchus contortus and Ascaris suum are parasitic nematodes that pose a considerable challenge to veterinary medicine. Unfortunately, the utility of each of the three major classes of broad-spectrum anthelmintic used to treat parasitic nematode infections (macrocyclic lactones, imidazothiazoles/ tetrahydropyrimidines, and benzimidazoles) is gradually eroding due to the emergence of strains of parasites that are resistant to the actions of these drugs. Mechanisms of drug resistance have been proposed for the benzimidazoles and the imidazothiazoles/ tetrahydropyrimidines (Prichard, 1990). However, the mechanism(s) for resistance to the macrocyclic lactones, such as ivermectin, in parasitic nematodes is still unknown. Recent studies suggest that multiple drug resistance (MDR) Pglycoproteins, transmembranous proteins that reduce the cytotoxic effects of drugs by actively transporting these compounds from cells, may underlie the mechanism of ivermectin resistance in parasitic nematodes (Sangster, 1993; Broeks et al., 1995; Sangster, 1995). In the present study, automated motility recordings and ivermectin absorption/disappearance kinetics in H. contortus along with ivermectin tissue distribution in A. suum were assessed in an effort to delineate this mechanism. Results of the motility recordings indicated an approximately 15-fold difference in ivermectin sensitivity between the wild-type and ivermectin-resistant strains of H. contortus in vitro; however, there was no significant difference in ivermectin absorption or disappearance kinetics between the two strains. The MDR inhibitor, cyclosporin A, had no significant effect on the kinetics of ivermectin in either strain of H. contortus. Additionally, there was no preferential distribution of ivermectin in the gut (or other tissues) of A. suum that would suggest MDR involvement. On the basis of these studies, we conclude that MDR Pglycoproteins are probably not responsible for ivermectin resistance in H. contortus and other parasitic nematodes.