Resistance to ivermectin has become a significant problem in many parts of the world, a problem that continues to grow with increase use of anthelmintics in animals and humans. Resistance to ivermectin may be conferred by the expression of P-glycoproteins. P-gp as it is commonly known is a membrane protein that has the ability to transport aromatic, hydrophobic drugs from cell membranes and cytoplasms. These proteins are considered to cause drug resistance in mammalian tumor cells and various parasites such as Plasmodium falciparum (Figure 1).
Figure 1. A schematic of how a P-glycoprotein would work within a cell.
In ivermectin resistance, the P-glycoproteins may work by binding to and
transporting ivermectin out of cells. Studies of Haemonchus contortus (a type
of sheep nematode) support this hypothesis. In the wild, many populations
of H. contortus have been found to be resistant. One study found that treatment
with ivermectin in H. contortus resulted in higher levels of P-glycoprotein
mRNA compared to unselected strains. P-glycoprotein gene structure was also
altered in the treatment group.(Xu, Molento et al. 1998)
Another method of conferring resistance may involve changes in the structure
of the glutamate-gated chloride channel themselves. At least one study has
found that treatment with Ivermectin results in selection pressures on the
gene for the alpha-subunit of the glutamate channel in H. contortus. (Blackhall,
Pouliot et al. 1998)
Figure 2. Resistance in Haemonchus contortus, a sheep nematode, is widespread.
Of particular concern to humans is the development of resistance in Onchocerca
vovulus, the parasite that causes River Blindess. . One study found the possibility
of selection for P-glycoprotein homologs and Beta-tubulin occurred in patients
infected with O. volvulus and treated with Ivermectin and another study found
small populations of treated individuals that do not clear infection completely.
(Eng and Prichard 2005) Thus far, there has been no solid documented evidence
of resistance to Ivermectin, but the potential for its development remains.
