Hostname: page-component-586b7cd67f-t8hqh Total loading time: 0 Render date: 2024-11-24T05:47:04.307Z Has data issue: false hasContentIssue false
  • English
  • Français

Comparative assessment of the access of albendazole, fenbendazole and triclabendazole to Fasciola hepatica: effect of bile in the incubation medium

Published online by Cambridge University Press:  19 January 2004

L. I. ALVAREZ ,
M. L. MOTTIER  and
C. E. LANUSSE
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, 7000, Tandil, Argentina
M. L. MOTTIER
Affiliation:
Consejo Nacional de Investigaciones Cientificas y Técnicas (CONICET), Argentina
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, 7000, Tandil, Argentina
Get access Rights & Permissions [Opens in a new window]

Abstract

The work reported here describes the comparative ability of albendazole (ABZ), fenbendazole (FBZ) and triclabendazole (TCBZ) to penetrate through the tegument of mature Fasciola hepatica, and the influence of the physicochemical composition of the incubation medium on the drug diffusion process. The data obtained from the trans-tegumental diffusion kinetic studies were complemented with the determination of lipid-to-water partition coefficients (octanol-water) for the benzimidazole (BZD) anthelmintic drugs assayed. Sixteen-week-old F. hepatica were obtained from untreated artificially infected sheep. The flukes were incubated (37 °C) over 60 and 90 min in incubation media (pH 7·4) prepared with different proportions of ovine bile and Krebs' Ringer Tris (KRT) buffer (100, 75, 50, 25 and 0% of bile) containing either ABZ, FBZ or TCBZ at a final concentration of 5 nmol/ml. After the incubation time expired, the liver fluke material was chemically processed and analysed by high performance liquid chromatography (HPLC) to measure drug concentrations within the parasite. Additionally, the octanol-water partition coefficients (PC) for each molecule were calculated (as an indicator of drug lipophilicity) using reversed phase HPLC. The 3 BZD molecules were recovered from F. hepatica at both incubation times in all incubation media assayed. The trans-tegumental diffusion of the most lipophilic molecules ABZ and FBZ (higher PC values) tended to be greater than that observed for TCBZ. Interestingly, the uptake of ABZ by the liver flukes was significantly greater than that measured for TCBZ, the most widely used flukicidal BZD compound. This differential uptake pattern may be a relevant issue to be considered to deal with TCBZ-resistant flukes. Drug concentrations measured within the parasite were lower in the incubations containing the highest bile proportions. The highest total availabilities of the 3 compounds were obtained in liver flukes incubated in the absence of bile. Altogether, these findings demonstrated that the entry of the drug into a target parasite may not only depend on a concentration gradient, the lipophilicity of the molecule and absorption surface, but also on the physicochemical composition of the parasite's surrounding environment.

Keywords

trans-tegumental drug diffusionbenzimidazole anthelminticsFasciola hepaticabile acidsalbendazolefenbendazoletriclabendazole
Type
Research Article
Information
Parasitology , Volume 128 , Issue 1 , January 2004 , pp. 73 - 81
Copyright
2004 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., SÁNCHEZ, S. & LANUSSE, C. (1999). In vivo and ex vivo uptake of albendazole and its sulphoxide metabolite by cestode parasites: relationship with their kinetic behaviour in sheep. Journal of Veterinary Pharmacology and Therapeutics 22, 77–86.CrossRefGoogle Scholar
ALVAREZ, L., IMPERIALE, F., SÁNCHEZ, S., MURNO, G. & LANUSSE, C. (2000). Uptake of albendazole and albendazole sulphoxide by Haemonchus contortus and Fasciola hepatica in sheep. Veterinary Parasitology 94, 75–89.CrossRefGoogle Scholar
ALVAREZ, L., MOTTIER, L., SÁNCHEZ, S. & LANUSSE, C. (2001). Ex vivo diffusion of albendazole and its sulphoxide metabolite into Ascaris suum and Fasciola hepatica. Parasitology Research 87, 929–934.Google Scholar
BAGGOT, D. (1982). Disposition and fate of drugs in the body. In Veterinary Pharmacology and Therapeutics (ed. Booth, N. H. & Mc Donald, L. E.), pp. 37. Iowa State University Press, Iowa.
BORAY, J., CROWFOOT, P., STRONG, M., ALLISON, J., SCHELLENBAUM, M., VON ORELLI, M. & SARASIN, G. (1983). Treatment of immature and mature Fasciola hepatica infections in sheep with triclabendazole. Veterinary Record 113, 315–317.CrossRefGoogle Scholar
BORGERS, M. & DE NOLLIN, S. (1975). Ultrastructural changes in Ascaris suum intestine after mebendazole treatment in vivo. Journal of Parasitology 60, 110–122.CrossRefGoogle Scholar
CALVOPINA, M., GUDERIAN, R., PAREDES, W., CHICO, M. & COOPER, P. (1998). Treatment of human pulmonary paragonimiasis with triclabendazole: clinical tolerance and drug efficacy. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 566–569.CrossRefGoogle Scholar
COLES, G. & STAFFORD, K. (2001). Activity of oxyclozanide, nitroxynil, clorsulon and albendazole against adult triclabendazole-resistant Fasciola hepatica. Veterinary Record 148, 723–724.CrossRefGoogle Scholar
CROSS, H., RENZ, A. & TREES, A. (1998). In vitro uptake of ivermectin by adult male Onchocerca ochengi. Annals of Tropical Medicine and Parasitology 92, 711–720.CrossRefGoogle Scholar
DEL ESTAL, J., ALVAREZ, A., VILLAVERDE, A. & PRIETO, J. (1993). Comparative effects of anionic, natural bile acid surfactants and mixed micelles on the intestinal absorption of the anthelmintic albendazole. International Journal of Pharmaceutics 91, 105–109.CrossRefGoogle Scholar
FETTERER, R., REW, R. & KNIGHT, H. (1982). Comparative efficacy of albendazole against Fasciola hepatica in sheep and calves: relationship to serum drug metabolite levels. Veterinary Parasitology 11, 309–316.CrossRefGoogle Scholar
FETTERER, R. & REW, R. (1984). Interaction of Fasciola hepatica with albendazole and its metabolites. Journal of Veterinary Pharmacology and Therapeutics 7, 113–118.CrossRefGoogle Scholar
FRIEDMAN, P. & PLATZER, E. (1980). Interaction of anthelmintic benzimidazoles with Ascaris suum embryonic tubulin. Biochimica et Biophysica Acta 630, 271–278.CrossRefGoogle Scholar
HENNESSY, D., LACEY, E., STEEL, J. & PRICHARD, R. (1987). The kinetics of triclabendazole disposition in sheep. Journal of Veterinary Pharmacology and Therapeutics 10, 64–72.CrossRefGoogle Scholar
HENNESSY, D., STEEL, J., LACEY, E., EAGLESON, G. & PRICHARD, R. (1989). The disposition of albendazole in sheep. Journal of Veterinary Pharmacology and Therapeutics 12, 421–429.CrossRefGoogle Scholar
HENNESSY, D., PRICHARD, R. & STEEL, J. (1993). Biliary secretion and enterohepatic recycling of fenbendazole metabolites in sheep. Journal of Veterinary Pharmacology and Therapeutics 16, 132–140.CrossRefGoogle Scholar
HO, N., GEARY, T., RAUB, T., BARSHUM, C. & THOMPSON, D. (1990). Biophysical transport properties of the cuticle of Ascaris suum. Molecular and Biochemical Parasitology 41, 153–166.CrossRefGoogle Scholar
HÖRTER, D. & DRESSMAN, J. (2001). Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Advanced Drug Delivery Reviews 46, 75–87.CrossRefGoogle Scholar
HORTON, R. (1990). Benzimidazoles in a wormy world. Parasitology Today 6, 106.CrossRefGoogle Scholar
LACEY, E. (1988). The role of the cytoskeletal protein tubulin in the mode of action and mechanism of drug resistance to benzimidazoles. International Journal for Parasitology 18, 885–936.CrossRefGoogle Scholar
LANUSSE, C. & PRICHARD, R. (1993). Clinical pharmacokinetics and metabolism of benzimidazole anthelmintics in ruminants. Drug Metabolism Reviews 25, 235–279.CrossRefGoogle Scholar
LUBEGA, G. & PRICHARD, R. (1991). Interaction of benzimidazole anthelmintics with Haemonchus contortus tubulin: binding affinity and anthelmintic efficacy. Experimental Parasitology 73, 203–213.CrossRefGoogle Scholar
McCRACKEN, R. & LIPKOWITZ, K. (1990). Structure-activity relationship of benzimidazole anthelmintics: a molecular modelling approach to in vivo drug efficacy. Journal of Parasitology 76, 853–864.CrossRefGoogle Scholar
McKELLAR, Q. & SCOTT, E. (1990). The benzimidazole anthelmintic agents – a review. Journal of Veterinary Pharmacology and Therapeutics 13, 223–247.CrossRefGoogle Scholar
MITCHELL, G., MARIS, L. & BONNIWELL, M. (1998). Triclabendazole-resistant liver fluke in Scottish sheep. Veterinary Record 143, 399.Google Scholar
MOLL, L., GAASENBEEK, C., VELLEMA, P. & BORGSTEEDE, F. (2000). Resistance of Fasciola hepatica against triclabendazole in cattle and sheep in the Netherlands. Veterinary Parasitology 91, 153–158.CrossRefGoogle Scholar
MOTTIER, L., ALVAREZ, L., PIS, A. & LANUSSE, C. (2003). Transtegumental diffusion of benzimidazole anthelmintics into Moniezia benedeni: correlation with their octanol-water partition coefficients. Experimental Parasitology 103, 1–7.CrossRefGoogle Scholar
OVEREND, D. & BOWEN, F. (1995). Resistance of Fasciola hepatica to triclabendazole. Australian Veterinary Journal 72, 275–276.CrossRefGoogle Scholar
PÉHOURCQ, F., THOMAS, J. & JARRY, C. (2000). A microscale HPLC method for the evaluation of octanol-water partition coefficients in a series of new 2-amino-2-oxazolines. Journal of Liquid Chromatography and Research Technology 23, 443–453.CrossRefGoogle Scholar
POELMA, F., BREAS, R., TUKKER, J. & CROMMELIN, J. (1991). Intestinal absorption of drugs. The influence of mixed micelles on the disappearance kinetics of drugs from the small intestine of the rat. Journal of Pharmacy and Pharmacology 43, 317–324.Google Scholar
QUELLETTE, M. (2001). Biochemical and molecular mechanisms of drug resistance in parasites. Tropical Medicine and International Health 6, 874–882.CrossRefGoogle Scholar
ROBERSON, E. & COURTNEY, C. (1995). Anticestodal and antitrematodal drugs. In Veterinary Pharmacology and Therapeutics (ed. Adams, R.), pp. 950–951. Iowa State University Press, Iowa.
ROBINSON, M., TRUDGETT, A., HOEY, E. & FAIRWEATHER, I. (2002). Triclabendazole-resistant Fasciola hepatica: β-tubulin and response to in vitro treatment with triclabendazole. Parasitology 124, 325–338.CrossRefGoogle Scholar
ROTHWELL, J. & SANGSTER, N. (1997). Haemonchus contortus: the uptake and metabolism of closantel. International Journal for Parasitology 27, 313–319.CrossRefGoogle Scholar
SIMS, S., HO, N., GEARY, T., THOMAS, E., DAY, J., BARSHUM, C. & THOMPSON, D. (1996). Influence of organic acid excretion on cuticle pH and drug absorption by Haemonchus contortus. International Journal for Parasitology 26, 25–35.CrossRefGoogle Scholar
SMITH, M. & CLEGG, J. (1981). Improved culture of Fasciola hepatica in vitro. Zeitschrift für Parasitenkunde 66, 9–15.CrossRefGoogle Scholar
SMITH, P., KROHN, R., HERMANSON, G., MALLIA, A., GARTNER, F., PROVENZANO, M., FUJIMOTO, E., GOEKE, N., OLSON, B. & KLENK, D. (1985). Measurement of protein using bicinchoninic acid. Analytical Biochemistry 150, 76–85.CrossRefGoogle Scholar
SOLANA, H., RODRIGUEZ, J. & LANUSSE, C. (2001). Comparative metabolism of albendazole and albendazole sulphoxide by different helminth parasites. Parasitology Research 87, 275–280.CrossRefGoogle Scholar
STITT, A. & FAIRWEATHER, I. (1994). The effect of the sulphoxide metabolite of triclabendazole (‘Fasinex’) on the tegument of mature and immature stages of the liver fluke, Fasciola hepatica. Parasitology 108, 555–567.CrossRefGoogle Scholar
THOMAS, I., COLES, G. & DUFFUS, K. (2000). Triclabendazole-resistant Fasciola hepatica in south-west Wales. Veterinary Record 146, 200.Google Scholar
THOMPSON, D., HO, N., SIMS, S. & GEARY, T. (1993). Mechanistic approaches to quantitate anthelmintic absorption by gastrointestinal nematodes. Parasitology Today 9, 31–35.CrossRefGoogle Scholar
THOMPSON, D. & GEARY, T. (1995). The structure and function of helminth surfaces. In Biochemistry and Molecular Biology of Parasites (ed. Marr, J. & Muller, M.), pp. 203–232. Academic Press Ltd, London.CrossRef
VIRKEL, G., IMPERIALE, F., LIFSCHITZ, A., PIS, A., ALVAREZ, A., MERINO, G., PRIETO, J. & LANUSSE, C. (2003). Effect of amphiphilic surfactant agents on the gastrointestinal absorption of albendazole in cattle. Biopharmaceutics and Drug Disposition 24, 95–103.CrossRefGoogle Scholar
WEBER, P., BUSCHER, G. & BUTTNER, D. (1988). The effects of triclabendazole on the lung fluke, Paragonimus uterobilateralis in the experimental host Sigmodon hispidus. Tropical Medicine and Parasitology 39, 322–324.Google Scholar
ZAJAC, A., SANGSTER, N. & GEARY, T. (2000). Why veterinarians should care more about parasitology? Parasitology Today 16, 504–506.Google Scholar