The Influence of the Apical Membrane P-Glycoprotein Efflux pump on Anthelmintics in MDCK Cell Monolayers
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Authors
Greenwald, Rachel
Issue Date
1995
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
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.
Description
vii, 52 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.