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P-glycoprotein interfering agents potentiate ivermectin susceptibility in ivermectin sensitive and resistant isolates of Teladorsagia circumcincta and Haemonchus contortus

Published online by Cambridge University Press:  24 June 2009

D. J. BARTLEY ,
H. McALLISTER ,
Y. BARTLEY ,
J. DUPUY ,
C. MÉNEZ ,
M. ALVINERIE ,
F. JACKSON  and
A. LESPINE
D. J. BARTLEY*
Affiliation:
Moredun Research Institute, Pentland Science Park, Bush Loan, Penicuik EH26 0PZ, UK
H. McALLISTER
Affiliation:
Moredun Research Institute, Pentland Science Park, Bush Loan, Penicuik EH26 0PZ, UK
Y. BARTLEY
Affiliation:
Moredun Research Institute, Pentland Science Park, Bush Loan, Penicuik EH26 0PZ, UK
J. DUPUY
Affiliation:
Laboratoire de Pharmacologie-Toxicologie, INRA, 180 chemin de Tournefeuille, 31931 Toulouse, France
C. MÉNEZ
Affiliation:
Laboratoire de Pharmacologie-Toxicologie, INRA, 180 chemin de Tournefeuille, 31931 Toulouse, France
M. ALVINERIE
Affiliation:
Laboratoire de Pharmacologie-Toxicologie, INRA, 180 chemin de Tournefeuille, 31931 Toulouse, France
F. JACKSON
Affiliation:
Moredun Research Institute, Pentland Science Park, Bush Loan, Penicuik EH26 0PZ, UK
A. LESPINE
Affiliation:
Laboratoire de Pharmacologie-Toxicologie, INRA, 180 chemin de Tournefeuille, 31931 Toulouse, France
*
*Corresponding author: Moredun Research Institute, Pentland Science Park, Bush Loan, Penicuik EH26 0PZ, UK. Tel: +44 131 445 5111. Fax: +44 131 445 6235. E-mail: dave.bartley@moredun.ac.uk
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Summary

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.

Keywords

ABC transportersP-glycoproteinanthelmintic resistanceivermectinTeladorsagia circumcinctaHaemonchus contortus
Type
Research Article
Information
Parasitology , Volume 136 , Issue 9 , August 2009 , pp. 1081 - 1088
Copyright
Copyright © Cambridge University Press 2009

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