The Influence of the Apical Membrane P-Glycoprotein Efflux pump on Anthelmintics in MDCK Cell Monolayers
The problem of resistance to broad-spectrum anthelmintics in the treatment of parasitic nematode infections is becoming more prevalent as the use of these anthelmintics increases and resistant animals are selected for. To solve this problem, mechanisms of resistance must be elucidated and overcome in some way. The mechanisms of resistance to benzimidazoles and levamisole deal with blocking drug binding sites and the reduction of drug-binding receptors, respectively. The mechanism is not known for ivermectin-resistance. However, studies have revealed that animals lacking the multidrug resistance p-glycoprotein are highly sensitive to ivermectin. Since this P-glycoprotein pump is often responsible for drug resistance, it may also be the mechanism for ivermectin resistance. The first step in finding if this pump is responsible for anthelmintic resistance in parasitic nematodes is to find which anthelmintics are substrates for the pump. The MDCK cell line can be used for this purpose since they asymetrically express these P-glycoproteins and form confluent monolayers. A directiionally polarized flux of an anthelmintic across the MDCK monlayer from the basolateral to the apical side compared to the flux from the apical to the basolateral side would suggest that that anthelmintic is a substrate. Ivermectin, levamisole, and three experimental compounds: U-88509, U-94119, and U-99437 were studied in this system to determine if they were substrates. Levamisole and U-88509 were not found to be substrates. U-99437 was found to inhibit the P-glycoprotein pump. Since inhibition is generally competitive in this system, U-99437 is most likely a substrate. U-94119 is questionable as a substrate, and ivermectin was found to be a substrate. These results suggest that the P-glycoprotein pump, if existent in nematodes, may play a role in resistance to ivermectin.
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