Hostname: page-component-78c5997874-m6dg7 Total loading time: 0 Render date: 2024-11-10T12:31:01.919Z Has data issue: false hasContentIssue false
  • English
  • Français

Effect of the metabolic inhibitor, methimazole on the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica

Published online by Cambridge University Press:  12 December 2008

C. DEVINE ,
G. P. BRENNAN ,
C. E. LANUSSE ,
L. I. ALVAREZ ,
A. TRUDGETT ,
E. HOEY  and
I. FAIRWEATHER
C. DEVINE
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
G. P. BRENNAN
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
C. E. LANUSSE
Affiliation:
Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000Tandil, Argentina
L. I. ALVAREZ
Affiliation:
Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000Tandil, Argentina
A. TRUDGETT
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
E. HOEY
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
I. FAIRWEATHER*
Affiliation:
Parasite Proteomics and Therapeutics Research Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland
*
*Corresponding author: School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BelfastBT9 7BL, Northern Ireland. Tel: +44 28 90972298. Fax: +44 28 90975877. E-mail: i.fairweather@qub.ac.uk
Get access Rights & Permissions [Opens in a new window]

Summary

A study has been carried out to investigate whether the action of triclabendazole (TCBZ) is altered in the presence of a metabolic inhibitor. The flavin monooxygenase system (FMO) was inhibited using methimazole (MTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-sensitive isolates were used for these experiments. The FMO system was inhibited by a 2-h pre-incubation in methimazole (100 μm). Flukes were then incubated for a further 22 h in NCTC medium containing either MTZ; MTZ+nicotinamide adenine dinucleotide phosphate (NADPH) (1 nm); MTZ+NADPH+TCBZ (15 μg/ml); or MTZ+NADPH+triclabendazole sulphoxide (TCBZ.SO) (15 μg/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment with either TCBZ or TCBZ.SO alone, there was greater surface disruption to the triclabendazole-susceptible than -resistant isolate. However, co-incubation with MTZ and TCBZ/TCBZ.SO lead to more severe surface changes to the TCBZ-resistant isolate than with each drug on its own; this was not seen for the TCBZ-susceptible Cullompton isolate. Results of this study support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance.

Keywords

Fasciola hepaticaliver fluketriclabendazole resistancemethimazolescanning electron microscopy
Type
Research Article
Information
Parasitology , Volume 136 , Issue 2 , February 2009 , pp. 183 - 192
Copyright
Copyright © 2008 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Alvarez, L. I., Solana, H. D., Mottier, M. L., Virkel, G. L., Fairweather, I. and Lanusse, C. E. (2005). Altered drug influx/efflux and enhanced metabolic activity in triclabendazole-resistant liver flukes. Parasitology 131, 501–510.CrossRefGoogle ScholarPubMed
Alvarez-Sanchez, M. A., Mainar-Jaime, R. C., Perez-Garcia, J. and Rojo-Vasquez, F. A. (2006). Resistance of Fasciola hepatica to triclabendazole and albendazole in sheep in Spain. Veterinary Record 159, 424–425.CrossRefGoogle ScholarPubMed
Bennett, C. E. (1975). Scanning electron microscopy of Fasciola hepatica L. during growth and maturation in the mouse. Journal of Parasitology 61, 892–898.Google Scholar
Fairweather, I. (2005). Triclabendazole: new skills to unravel an old(ish) enigma. Journal of Helminthology 79, 227–234.CrossRefGoogle ScholarPubMed
Fairweather, I., Threadgold, L. T. and Hanna, R. E. B. (1999). Development of Fasciola hepatica in the mammalian host. In Fasciolosis (ed. Dalton, J. P.), pp. 47–111. CAB International, Wallingford, Oxon, UK.Google Scholar
Halferty, L., Brennan, G. P., Hanna, R. E. B., Edgar, H. W., Meaney, M. M., McConville, M., Trudgett, A., Hoey, L. and Fairweather, I. (2008 a). Tegumental surface changes in juvenile Fasciola hepatica in response to treatment in vivo with triclabendazole. Veterinary Parasitology 155, 49–58.Google Scholar
Halferty, L., Brennan, G. P., Trudgett, A., Hoey, L. and Fairweather, I. (2008 b). The relative activity of triclabendazole metabolites against the liver fluke, Fasciola hepatica. Veterinary Parasitology (in the Press).Google ScholarPubMed
Hennessy, D. R., Lacey, E., Steel, J. W. and Prichard, R. K. (1987). The kinetics of triclabendazole disposition in sheep. Journal of Veterinary Pharmacology and Therapeutics 10, 64–72.Google Scholar
Keiser, J., Utzinger, J., Vennerstrom, J. L., Dong, Y., Brennan, G. P. and Fairweather, I. (2007). Activity of artemether and OZ78 against triclabendazole-resistant Fasciola hepatica. Transactions of the Royal Society of Tropical Medicine and Hygiene 101, 1219–1222.Google Scholar
Lanusse, C. E. and Prichard, R. K. (1992 a). Effects of methimazole on the kinetics of netobimin metabolites in cattle. Xenobiotica 22, 115–123.Google Scholar
Lanusse, C. E. and Prichard, R. K. (1992 b). Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep. Biopharmaceutics and Drug Disposition 13, 95–103.Google Scholar
Lanusse, C. E. and Prichard, R. K. (1993). Clinical pharmacokinetics and metabolism of benzimidazole anthelmintics in ruminants. Drug Metabolism Reviews 25, 235–279.Google Scholar
Lanusse, C. E., Gascon, L. and Prichard, R. K. (1992). Methimazole-mediated modulation of netobimin biotransformation in sheep: a pharmacokinetic assessment. Journal of Veterinary Pharmacology and Therapeutics 15, 267–274.CrossRefGoogle ScholarPubMed
Lanusse, C. E., Gascon, L. H. and Prichard, R. K. (1995). Influence of the antithyroid compound methimazole on the plasma disposition of fenbendazole and oxfendazole in sheep. Research in Veterinary Science 58, 222–226.Google Scholar
López-García, M. L., Torrado, S., Torrado, S., Martínez, A. R. and Bolás, F. (1998). Methimazole-mediated enhancement of albendazole oral bioavailability and anthelmintic effects against parenteral stages of Trichinella spiralis in mice: the influence of the dose-regime. Veterinary Parasitology 75, 209–219.CrossRefGoogle ScholarPubMed
Mas-Coma, S., Bargues, M. D. and Valero, M. A. (2005). Fascioliasis and other plant-borne trematode zoonoses. International Journal for Parasitology 35, 1255–1278.Google Scholar
McCoy, M. A., Fairweather, I., Brennan, G. P., Kenny, J. M., Ellison, S. and Forbes, A. B. (2005). The efficacy of nitroxynil and triclabendazole administered synchronously against juvenile triclabendazole-resistant Fasciola hepatica in sheep. Research in Veterinary Science 78 (Suppl. A), 33.Google Scholar
Mottier, L., Alvarez, L., Ceballos, L. and Lanusse, C. (2006 a). Drug transport mechanisms in helminth parasites: passive diffusion of benzimidazole anthelmintics. Experimental Parasitology 113, 49–57.Google Scholar
Mottier, L., Alvarez, L., Fairweather, I. and Lanusse, C. (2006 b). Resistance-induced changes in triclabendazole transport in Fasciola hepatica: ivermectin reversal effect. Journal of Parasitology 92, 1355–1360.Google Scholar
Murphy, T., Fahy, K. N., Mc Auliffe, A., Forbes, A. B., Clegg, T. A. and O'Brien, D. J. (2006). A study of helminth parasites in culled cows in Ireland. Preventative Veterinary Medicine 76, 1–10.Google Scholar
Robinson, M. W., Lawson, J., Trudgett, A., Hoey, E. M. and Fairweather, I. (2004). The comparative metabolism of triclabendazole sulphoxide by triclabendazole-susceptible and triclabendazole-resistant Fasciola hepatica. Parasitology Research 92, 205–210.Google Scholar
Robinson, M. W., Trudgett, A., Hoey, E. M. and Fairweather, I. (2002). Triclabendazole-resistant Fasciola hepatica: β-tubulin and response to in vitro treatment with triclabendazole. Parasitology 124, 325–338.Google Scholar
Ryan, L., Hoey, E., Trudgett, A., Fairweather, I., Fuchs, M., Robinson, M. W., Chambers, E., Timson, D. J., Ryan, E., Feltwell, T., Ivens, A., Bentley, G. and Johnston, D. (2008). Fasciola hepatica expresses multiple α- and β-tubulin isotypes. Molecular and Biochemical Parasitology 159, 73–78.Google Scholar
Toner, E., McConvery, F., Brennan, G. P., Meaney, M. and Fairweather, I. (2008). A scanning electron microscope study on the route of entry of triclabendazole into the liver fluke, Fasciola hepatica. Parasitology (in the Press).Google Scholar
Tynes, R. E. and Hodgson, E. (1983). Oxidation of thiobenzamide by the FAD-containing and cytochrome P-450 dependent mono-oxygenases of liver and lung microsomes. Biochemical Pharmacology 32, 3419–3428.Google Scholar
Virkel, G., Lifschitz, A., Sallovitz, J., Pis, A. and Lanusse, C. (2006). Assessment of the main metabolism pathways for the flukicidal compound triclabendazole in sheep. Journal of Veterinary Pharmacology and Therapeutics 29, 213–223.Google Scholar
Virkel, G., Lifschitz, A., Sallovitz, J., Ballent, M., Scarcella, S. and Lanusse, C. (2008). Inhibition of cytochrome P450 activity enhances the systemic availability of triclabendazole metabolites in sheep. Journal of Veterinary Pharmacology and Therapeutics (in the Press).Google Scholar
Walker, S. M., McKinstry, B., Boray, J. C., Brennan, G. P., Trudgett, A., Hoey, E. M., Fletcher, H. and Fairweather, I. (2004). Response of two isolates of Fasciola hepatica to treatment with triclabendazole in vivo and in vitro. Parasitology Research 94, 427–438.Google Scholar