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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: [email protected]
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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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References

REFERENCES

Alvarez-Sanchez, M. A., Perez Garcia, J., Bartley, D., Jackson, F. and Rojo-Vazquez, F. A. (2005). The larval feeding inhibition assay for the diagnosis of nematode anthelmintic resistance. Experimental Parasitology 110, 56–61.CrossRefGoogle ScholarPubMed
Ballent, M., Lifschitz, A., Virkel, G., Sallovitz, J. and Lanusse, C. (2006). Modulation of the P-glycoprotein-mediated intestinal secretion of ivermectin: in vitro and in vivo assessments. Drug Metabolism and Disposition 34, 457–463.CrossRefGoogle ScholarPubMed
Bartley, D. J., Jackson, E., Johnston, K., Coop, R. L., Mitchell, G. B., Sales, J. and Jackson, F. (2003). A survey of anthelmintic resistant nematode parasites in Scottish sheep flocks. Veterinary Parasitology 117, 61–71.CrossRefGoogle ScholarPubMed
Bartley, D. J., Jackson, E., Sargison, N. and Jackson, F. (2005). Further characterisation of a triple resistant field isolate of Teladorsagia from a Scottish lowland sheep farm. Veterinary Parasitology 134, 261–266.CrossRefGoogle ScholarPubMed
Bartley, D. J., Dupuy, J., Alvinerie, M., Jackson, F. and Lespine, A. (2009). The influence of ketoconazole and pluronic 85 on the efficacy and pharmacokinetics of ivermectin in Haemonchus contortus infected lambs. Proceedings of British Society for Parasitology, Joint Malaria and Spring Meeting, Edinburgh, 5–7 April 2009, S8, 50.Google Scholar
Benchaoui, H. A. and McKellar, Q. A. (1996). Interaction between fenbendazole and piperonyl butoxide: pharmacokinetic and pharmacodynamic implications. Journal of Pharmacy and Pharmacology 48, 753–759.CrossRefGoogle ScholarPubMed
Beugnet, F., Gauthey, M. and Kerboeuf, D. (1997). Partial in vitro reversal of benzimidazole resistance by the free-living stages of Haemonchus contortus with verapamil. Veterinary Record 141, 575–576.CrossRefGoogle ScholarPubMed
Blackhall, W. J., Liu, H. Y., Xu,M. ,M., Prichard, R. K. and Beech, R. N. (1998). Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus. Molecular and Biochemical Parasitology 95, 193–201.CrossRefGoogle Scholar
Borgsteede, F. H. and Couwenberg, T. (1987). Changes in LC50 in an in vitro egg development assay during the patent period of Haemonchus contortus in sheep. Research in Veterinary Science 42, 413–414.CrossRefGoogle Scholar
Borst, P., Evers, R., Kool, M. and Wijnholds, J. (1999). The multidrug resistance protein family. Biochimica et Biophysica Acta 1461, 347–357.CrossRefGoogle ScholarPubMed
Broeks, A., Janssen, H. W., Calafat, J. and Plasterk, R. H. (1995). A P-glycoprotein protects Caenorhabditis elegans against natural toxins. The EMBO Journal 14, 1858–1866.CrossRefGoogle ScholarPubMed
Didier, A. and Loor, F. (1996). The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor. Anticancer Drugs 7, 745–751.CrossRefGoogle ScholarPubMed
Dupuy, J., Larrieu, G., Sutra, J. F., Lespine, A. and Alvinerie, M. (2003). Enhancement of moxidectin bioavailability in lamb by a natural flavonoid: quercetin. Veterinary Parasitololgy 112, 337–347.CrossRefGoogle ScholarPubMed
Freeman, A. S., Nghiem, C., Li, J., Ashton, F. T., Guerrero, J., Shoop, W. L. and Schad, G. A. (2003). Amphidial structure of ivermectin-resistant and susceptible laboratory and field strains of Haemonchus contortus. Veterinary Parasitololgy 110, 217–226.CrossRefGoogle ScholarPubMed
Geary, T. G., Sims, S. M., Thomas, E. M., Vanover, L., Davis, J. P., Winterrowd, C. A., Klein, R. D., Ho, N. F. and Thompson, D. P. (1993). Haemonchus contortus: ivermectin-induced paralysis of the pharynx. Experimental Parasitology 77, 88–96.CrossRefGoogle ScholarPubMed
Geary, T. G. (2005). Ivermectin 20 years on: maturation of a wonder drug. Trends in Parasitology 21, 530–532.CrossRefGoogle ScholarPubMed
Gill, J. H., Redwin, J. M., van Wyk, J. A. and Lacey, E. (1995). Avermectin inhibition of larval development in Haemonchus contortus – effects of ivermectin resistance. International Journal for Parasitology 25, 463–470.CrossRefGoogle ScholarPubMed
Gill, J. H., Kerr, C. A., Shoop, W. L. and Lacey, E. (1998). Evidence of multiple mechanisms of avermectin resistance in Haemonchus contortus – comparison of selection protocols. International Journal for Parasitology 28, 783–789.CrossRefGoogle ScholarPubMed
Gill, J. H. and Lacey, E. (1998). Avermectin/milbemycin resistance in trichostrongyloid nematodes. International Journal for Parasitology 28, 863–877.CrossRefGoogle ScholarPubMed
Gottesman, M. M. and Pastan, I. (1993). Biochemistry of multidrug resistance mediated by the multidrug transporter. Annual Review of Biochemistry 62, 385–427.CrossRefGoogle ScholarPubMed
Guerrero, J. and Freeman, A. S. (2004). Amphids: the neuronal ultrastructure of macrocyclic-lactone-resistant Haemonchus contortus. Parasitologia 46, 237–240.Google ScholarPubMed
Hsiu, S. L., Hou, Y. C., Wang, Y. H., Tsao, C. W., Su, S. F. and Chao, P. D. (2002). Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. Life Sciences 72, 227–235.CrossRefGoogle Scholar
Jabbar, A., Iqbal, Z., Kerboeuf, D., Muhammad, G., Khan, M. N. and Afaq, M. (2006). Anthelmintic resistance: the state of play revisited. Life Sciences 79, 2413–2431.CrossRefGoogle ScholarPubMed
Jackson, F., Coop, R. L., Jackson, E., Scott, E. W. and Russel, A. J. (1992). Multiple anthelmintic resistant nematodes in goats. Veterinary Record 130, 210–211.CrossRefGoogle ScholarPubMed
Jackson, F. and Coop, R. L. (2000). The development of anthelmintic resistance in sheep nematodes. Parasitology 120 (Suppl.), S95–S107.CrossRefGoogle ScholarPubMed
James, C. E. and Davey, M. W. (2009). Increased expression of ABC transport proteins is associated with ivermectin resistance in the model nematode Caenorhabditis elegans. International Journal for Parasitology 39, 213–220.CrossRefGoogle ScholarPubMed
Kabanov, A. V., Batrakova, E. V., Sriadibhatla, S., Yang, Z., Kelly, D. L. and Alakov, V. Y. (2005). Polymer genomics: shifting the gene and drug delivery paradigms. Journal of Controlled Release 101, 259–271.CrossRefGoogle ScholarPubMed
Kaplan, R. M. (2004). Drug resistance in nematodes of veterinary importance: a status report. Trends in Parasitology 20, 477–481.CrossRefGoogle ScholarPubMed
Kerboeuf, D., Hubert, J. and Mallet, S. (1989). Haemonchus contortus: infectivity and resistance to benzimidazoles. Veterinary Record 124, 399–400.CrossRefGoogle ScholarPubMed
Kerboeuf, D., Guegnard, F. and Le Vern, Y. (2002). Analysis and partial reversal of multidrug resistance to anthelmintics due to P-glycoprotein in Haemonchus contortus eggs using Lens culinaris lectin. Parasitology Research 88, 816–821.Google ScholarPubMed
Kerboeuf, D., Blackhall, W., Kaminsky, R. and von Samson-Himmelstjerna, G. (2003). P-glycoprotein in helminths: function and perspectives for anthelmintic treatment and reversal of resistance. International Journal of Antimicrobial Agents 22, 332–346.CrossRefGoogle ScholarPubMed
Kotze, A. C. (1998). Effects of macrocyclic lactones on ingestion in susceptible and resistant Haemonchus contortus larvae. Journal of Parasitology 84, 631–635.CrossRefGoogle ScholarPubMed
Kotze, A. C., Dobson, R. J., Tyrrell, K. L. and Stein, P. A. (2002). High-level ivermectin resistance in a field isolate of Haemonchus contortus associated with a low level of resistance in the larval stage: implications for resistance detection. Veterinary Parasitology 108, 255–263.CrossRefGoogle Scholar
Lanusse, C. E. and Prichard, R. K. (1993). Clinical pharmacokinetics and metabolism of benzimidazole anthelmintics in ruminants. Drug Metabolism Reviews 25, 235–279.CrossRefGoogle ScholarPubMed
Lautier, D., Canitrot, Y., Deeley, R. G. and Cole, S. P. (1996). Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. Biochemical Pharmacology 52, 967–977.CrossRefGoogle ScholarPubMed
Le Jambre, L. F., Gill, J. H., Lenane, I. J. and Lacey, E. (1995). Characterisation of an avermectin resistant strain of Australian Haemonchus contortus. International Journal for Parasitology 25, 691–698.CrossRefGoogle ScholarPubMed
Le Jambre, L. F., Dobson, R. J., Lenane, I. J. and Barnes, E. H. (1999). Selection for anthelmintic resistance by macrocyclic lactones in Haemonchus contortus. International Journal for Parasitology 29, 1101–1111.CrossRefGoogle ScholarPubMed
Lespine, A., Dupuy, J., Orlowski, S., Nagy, T., Glavinas, H., Krajcsi, P. and Alvinerie, M. (2006). Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3). Chemico-biological Interactactions 159, 169–179.CrossRefGoogle ScholarPubMed
Lespine, A., Martin, S., Dupuy, J., Roulet, A., Pineau, T., Orlowski, S. and Alvinerie, M. (2007). Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. European Journal of Pharmacological Science 30, 84–94.CrossRefGoogle ScholarPubMed
Lespine, A., Alvinerie, M., Vercruysse, J., Prichard, R. K. and Geldhof, P. (2008). ABC transporter modulation: a strategy to enhance the activity of macrocyclic lactone anthelmintics. Trends in Parasitology 24, 293–298.CrossRefGoogle ScholarPubMed
Lifschitz, A., Virkel, G., Sallovitz, J., Imperiale, F., Pis, A. and Lanusse, C. (2002). Loperamide-induced enhancement of moxidectin availability in cattle. Journal of Veterinary Pharmacology and Therapeutics 25, 111–120.CrossRefGoogle ScholarPubMed
Lifschitz, A., Sallovitz, J., Imperiale, F., Suarez, V., Cristel, S., Ahoussou, S. and Lanusse, C. (2007). Modulation of P-glycoprotein enhances ivermectin and moxidectin systemic availabilities and their efficacy against resistant nematodes. Proceedings of the 21st International Conference of the World Association for the Advancement of Veterinary Parasitology 23, 141.Google Scholar
Molento, M. B. and Prichard, R. K. (1999). Effects of the multidrug-resistance-reversing agents verapamil and CL 347,099 on the efficacy of ivermectin or moxidectin against unselected and drug-selected strains of Haemonchus contortus in jirds (Meriones unguiculatus). Parasitology Research 85, 1007–1011.CrossRefGoogle ScholarPubMed
Molento, M. B., Lifschitz, A., Sallovitz, J., Lanusse, C. and Prichard, R. (2004). Influence of verapamil on the pharmacokinetics of the antiparasitic drugs ivermectin and moxidectin in sheep. Parasitology Research 92, 121–127.CrossRefGoogle ScholarPubMed
Prichard, R. K. (2005). Is anthelmintic resistance a concern for heartworm control? What can we learn from the human filariasis control programs? Veterinary Parasitology 133, 243–253.CrossRefGoogle ScholarPubMed
Prichard, R. K. (2007). Ivermectin resistance and overview of the consortium for anthelmintic resistance SNPs. Expert Opinion on Drug Discovery 2, S41–S52.CrossRefGoogle Scholar
Prichard, R. K. and Roulet, A. (2007). ABC transporters and beta-tubulin in macrocyclic lactone resistance: prospects for marker development. Parasitology 134, 1123–1132.CrossRefGoogle ScholarPubMed
Rothwell, J. and Sangster, N. (1997). Haemonchus contortus: the uptake and metabolism of closantel. International Journal for Parasitology 27, 313–319.CrossRefGoogle ScholarPubMed
Sangster, N. (1996). Pharmacology of anthelmintic resistance. Parasitology 113 (Suppl.), S201–S216.CrossRefGoogle ScholarPubMed
Sangster, N. C., Bannan, S. C., Weiss, A. S., Nulf, S. C., Klein, R. D. and Geary, T. G. (1999). Haemonchus contortus: sequence heterogeneity of internucleotide binding domains from P-glycoproteins. Experimental Parasitology 91, 250–257.CrossRefGoogle ScholarPubMed
Sangster, N. C., Song, J. and Demeler, J. (2005). Resistance as a tool for discovering and understanding targets in parasite neuromusculature. Parasitology 131 (Suppl.), S179–S190.CrossRefGoogle ScholarPubMed
Scott, E. W., Bairden, K., Holmes, P. H. and McKellar, Q. A. (1989). Benzimidazole resistance in nematodes of goats. Veterinary Record 124, 492.CrossRefGoogle ScholarPubMed
Scott, J. G. (1989). Cross-resistance to the biological insecticide abamectin in pyrethroid-resistant house flies. Pesticide Biochemistry and Physiology 34, 27–31.CrossRefGoogle Scholar
Seelig, A., Blatter, X. L. and Wohnsland, F. (2000). Substrate recognition by P-glycoprotein and the multidrug resistance-associated protein MRP1: a comparison. International Journal of Clinical Pharmacology & Therapeutics 38, 111–121.CrossRefGoogle ScholarPubMed
Sheriff, J. C., Kotze, A. C., Sangster, N. C. and Martin, R. J. (2002). Effects of macrocyclic lactone anthelmintics on feeding and pharyngeal pumping in Trichostrongylus colubriformis in vitro. Parasitology 125, 477–484.CrossRefGoogle ScholarPubMed
Shoop, W. L., Haines, H. W., Michael, B. F. and Eary, C. H. (1993). Mutual resistance to avermectins and milbemycins: oral activity of ivermectin and moxidectin against ivermectin-resistant and susceptible nematodes. Veterinary Record 133, 445–447.CrossRefGoogle ScholarPubMed
Sutherland, I. A., Brown, A. E., Leathwick, D. M. and Bisset, S. A. (2003). Resistance to prophylactic treatment with macrocyclic lactone anthelmintics in Teladorsagia circumcincta. Veterinary Parasitology 115, 301–309.CrossRefGoogle ScholarPubMed
van Wyk, J. A., Malan, F. S., Gerber, H. M. and Alves, R. M. (1987). Two field strains of Haemonchus contortus resistant to rafoxanide. Onderstepoort Journal of Veterinary Research 54, 143–146.Google ScholarPubMed
Virkel, G., Lifschitz, A., Sallovitz, J., Ballent, M., Scarcella, S. and Lanusse, C. (2009). Inhibition of cytochrome P450 activity enhances the systemic availability of triclabendazole metabolites in sheep. Journal of Veterinary Pharmacology and Therapeutics 32, 79–86.CrossRefGoogle ScholarPubMed
von Samson-Himmelstjerna, G. (2006). Molecular diagnosis of anthelmintic resistance. Veterinary Parasitology 136, 99–107.CrossRefGoogle ScholarPubMed
Ward, K. W., Stelman, G. J., Morgan, J. A., Zeigler, K. S., Azzarano, L. M., Kehler, J. R., McSurdy-Freed, J. E., Proksch, J. W. and Smith, B. R. (2004). Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey. Drug Metabolism and Disposition 32, 172–177.CrossRefGoogle Scholar
Wolstenholme, A. J., Fairweather, I., Prichard, R., von Samson-Himmelstjerna, G. and Sangster, N. C. (2004). Drug resistance in veterinary helminths. Trends in Parasitology 20, 469–476.CrossRefGoogle ScholarPubMed
Xu, M., Molento, M., Blackhall, W., Ribeiro, P., Beech, R. and Prichard, R. (1998). Ivermectin resistance in nematodes may be caused by alteration of P-glycoprotein homolog. Molecular and Biochemical Parasitology 91, 327–335.CrossRefGoogle ScholarPubMed
Yates, D. M., Portillo, V. and Wolstenholme, A. J. (2003). The avermectin receptors of Haemonchus contortus and Caenorhabditis elegans. International Journal for Parasitology 33, 1183–1193.CrossRefGoogle ScholarPubMed