Abstract
Netobimin (NTB) was administered orally to ewes at 20 mg/kg bodyweight. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high-performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of albendazole sulphoxide (ABZSO) enantiomers produced was also determined. Neither NTB nor albendazole (ABZ) was present and only ABZSO and albendazole sulphone (ABZSO2) metabolites were detected in the plasma samples. Maximum plasma concentrations (C<max) of ABZSO (4.1 ± 0.7 μg/ml) and ABZSO2 (1.1 ± 0.4 μg/ml) were detected at (t max) 14.7 and 23.8 h, respectively following oral administration of netobimin. The area under the curve (AUC) of ABZSO (103.8 ± 22.8 (μg h)/ml) was significantly higher than that ABZSO2(26.3± 10.1 (μg h)/ml) (p<0.01). (−)−ABZSO and (+)-ABZSO enantiomers were never in racemate proportions in plasma. The AUC of (+)-ABZSO (87.8±20.3 (μg h)/ml) was almost 6 times larger than that of (−)−ABZSO (15.5 ±5.1 (μg h)/ml) (p < 0.001). Netobimin was not detected, and ABZ was predominant and its AUC was significantly higher than that of ABZSO and ABZSO2, following NTB administration in faecal samples (p > 0.01). Unlike in the plasma samples, the proportions of the enantiomers of ABZSO were close to racemic and the ratio of the faecal AUC of (−)−ABZSO (172.22 ±57.6 (μg h)/g) and (+)-ABZSO (187.19 ±63.4 (μg h)/g) was 0.92. It is concluded that NTB is completely converted to ABZ by the gastrointestinal flora and absorbed ABZ is completely metabolized to its sulphoxide and sulphone metabolites by first-pass effects. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver that are responsible for sulphoxidation and sulphonation of ABZ.
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Abbreviations
- ABZ:
-
albendazole
- ABZSO:
-
albendazole sulphoxide
- ABZSO2 :
-
albendazole sulphone
- AUC:
-
area under the plasma concentration–time curve
- AUMC:
-
area under the first moment curve
- DMSO:
-
dimethyl sulphoxide
- FBZSO:
-
oxfendazole
- FMO:
-
flavin-containing monooxygenase
- HPLC:
-
high-performance liquid chromatography
- MRT:
-
mean residence time
- NTB:
-
netobimin
References
Alvarez, L., Sanchez, S. and Lanusse, C., 1999. In vivo and ex vivo uptake of albendazole and its sulphoxide metabolite by cestode parasites: relationship with their kinetics behaviour in sheep. Journal of Veterinary Pharmacology and Therapeutics 22, 77–86
Alvarez, L., Imperiale, F., Sanchez, S., Murno, G. and Lanusse, C., 2000. Uptake of albendazole and albendazole sulphoxide by Haemonchus contortus and Fasciola hepatica in sheep. Veterinary Parasitology 94 75– 89
Benoit, E., Besse, S. and Delatour, P., 1992. Effect of repeated doses of albendazole on enantiomerism of its sulphoxide metabolite in goats. American Journal of Veterinary Research, 53, 1663–1665.
Blume, R.R., Younger, R.L., Aga, A. and Myers, C.J., 1976. Effects of residues of certain anthelmintics in bovine manure on Onthophagus gazella, a non-target organism. Southwest Entomologist, 1, 100–103
Capece, B.P., Calsamiglia, S., Castells, G., Arboix, M. and Cristofol, C., 2001. Effect of ruminal microflora on the biotransformation of netobimin, albendazole, albendazole sulfoxide, and albendazole sulfoxide enantiomers in an artificial rumen. Journal of Animal Science, 79, 1288–1294
Cristofol, C., Carretero, A., Fernandez, M., Navarro, M., Sautet, J., Ruberte, J. and Arboix, M., 1995. Transplacental transport of netobimin metabolites in ewes. European Journal of Drug Metabolism and Pharmacokinetics, 20, 167–171
Cristofol, C., Franquelo, C., Navarro, M., Carretero, A., Ruberte, J. and Arboix, M., 1997. Comparative pharmacokinetics of netobimin metabolites in pregnant ewes. Research in Veterinary Science, 62, 117–120
Delatour, P. and Parish, R., 1986. Benzimidazole anthelmintics and related compounds: toxicity and evaluation of residues. In: A.G. Rico (ed.), Drug Residues in Animals, (Academic Press, New York), 175–203
Delatour, P., Cure, M.C., Benoit, E. and Garnier, F., 1986. Netobimin (Totabin-SCH): preliminary investigation on metabolism and pharmacology. Journal of Veterinary Pharmacology and Therapeutics, 9, 230– 234
Delatour, P., Benoit, E., Garnier, F. and Besse, S., 1990. Chirality of the sulphoxide metabolites of fenbendazole and albendazole in sheep. Journal of Veterinary Pharmacology and Therapeutics, 13, 361–366
Delatour, P., Garnier, F., Benoit, E. and Caude, I., 1991a. Chiral behaviour of the metabolite albendazole sulphoxide in sheep, goats and cattle. Research in Veterinary Science, 50, 134–138
Delatour, P., Benoit, E., Besse, S. and Boukraa, A., 1991b. Comparative enantioselectivity in the sulphoxidation of albendazole in man, dogs and rats. Xenobiotica, 21, 217–221
Delatour, P., Benoit, E. and Soraci, A., 1994. Reckebusch Memorial Lecture: Drug chirality: its significance in veterinary pharmacology and therapeutics. In: P. Lees (ed.), Proceedings of the 6th International Congress of the European Association for Veterinary Pharmacology and Toxicology, (Blackwell Scientific, Edinburgh) 6–9
Duwel, D., 1977. Fenbendazole II, biological properties and activity. Pesticide Science, 8, 550–555
Galtier, P., Alvinerie, M. and Delatour, P., 1986. In vitro sulphoxidation of albendazole by ovine liver microsomes: assay and frequency of various xenobiotics. American Journal of Veterinary Research, 47, 447–450
Galtier, P., Alvinerie, M., Steimer, J.L., Francheteau, P., Plusquellec, Y. and Houin, G., 1991. Simultaneous pharmacokinetic modeling of a drug and two metabolites: application to albendazole in sheep. Journal of Pharmacological Science, 80, 3–10
Gokbulut, C., Nolan, A.M. and McKellar, Q.A., 2002. Pharmacokinetic disposition, faecal excretion and in vitro metabolism of oxibendazole following oral administration in horses. Research in Veterinary Science, 72, 11– 15
Goudah, A., 2003. Aspects of the pharmacokinetics of albendazole sulphoxide in sheep. Veterinary Research Communications, 27, 555–566
Hanafy, A., Langguth, P. and Spahn-Langguth, H., 2001. Pretreatment with potent P-glycoprotein ligands may increase intestinal secretion in rats. European Journal of Pharmacological Science, 12, 405–415
Hennessy, D.R., Sangster, N.C., Steel, J.W. and Collins, G.W., 1993a. Comparative pharmacokinetic behaviour of albendazole in sheep and goats. International Journal of Parasitoloji, 23, 321–325
Hennessy, D.R., Sangster, N.C., Steel, J.W. and Collins, G.W., 1993b. Comparative kinetic disposition of oxfendazole in sheep and goat before and during infection with Haemonchus contortus and Trichostrongylus colubriformis. Journal of Veterinary Pharmacology and Therapeutics, 16, 245–250
Hennessy, D.R., Steel, J.W. and Prichard, R.K., 1993c. Biliary secretion and enterohepatic recycling of fenbendazole metabolites in sheep. Journal of Veterinary Pharmacology and Therapeutics, 16, 132–140
Lacey, E., Brady, R.L., Prichard, R.K. and Watson, T.R., 1987. Comparison of inhibition of polymerisation of mammalian tubulin and helminth ooicidal activity by benzimidazole carbonates. Veterinary Parasitology, 23, 105–119
Landoni, M.F., Soraci, A.L., Delatour, P. and Lees, P., 1997. Enantioselective behaviour of drugs used in domestic animals, a review. Journal of Veterinary Pharmacology and Therapeutics, 20, 1–16
Lanusse, C.E. and Prichard, R.K., 1990. Pharmacokinetic behaviour of netobimin and its metabolites in sheep. Journal of Veterinary Pharmacology and Therapeutics, 13, 170–178
Lanusse, C.E. and Prichard, R.K., 1992. Effects of methimazole on the kinetics of netobimin metabolites in cattle. Xenobiotica, 22, 115–123
Lanusse, C.E. and Prichard, R.K., 1993. Relationship between pharmacological properties and clinical efficacy of ruminant anthelmintics. Veterinary Parasitology, 49, 123–158
Lanusse, C.E., Nare, B., Gascon, L.H. and Prichard, R.K., 1992. Metabolism of albendazole and albendazole sulphoxide by ruminal and intestinal fluids of sheep and cattle. Xenobiotica, 22, 419–426
Lanusse, C.E., Gascon, L.H., and Prichard, R.K., 1993. Gastrointestinal distribution of albendazole metabolites following netobimin administration to cattle: relationship with plasma disposition kinetics. Journal of Veterinary Pharmacology and Therapeutics, 16, 38–47
Marriner, S.E. and Bogan, J.A., 1980. Pharmacokinetics of albendazole in sheep. American Journal of Veterinary Research, 41, 483–491
McKellar, Q.A., 1997. Ecotoxicology and residues of anthelmintic compounds. Veterinary Parasitology, 72, 413–435
McKellar, Q.A. and Scott, E.W., 1990. The benzimidazole anthelmintic agents: a review. Journal of Veterinary Pharmacology and Therapeutics, 13, 223–247
McKellar, Q.A., Jackson, F., Coop, R.L. and Baggot, J.D., 1993. Plasma profiles of albendazole metabolites after administration of netobimin and albendazole in sheep, effects of parasitism and age. British Veterinary Journal, 149, 101–113
McKellar, Q.A., Gokbulut, C., Muzandu, K. and Benchaoui, H., 2002. Fenbendazole pharmacokinetics, metabolism, and potentiation in horses. Drug Metabolism and Disposition. 30, 1230–1239
Merino, G., Alvarez, A.I., Redondo, P.A., Garcia, J.L., Larrode, O.M. and Prieto, J.G., 1999. Bioavailability of albendazole sulphoxide after netobimin administration in sheep, effects of fenbendazole coadministration. Research in Veterinary Science, 66, 281–283
Merino, G., Alvarez, A.I., Prieto, J.G. and Kim, R.B., 2002. The anthelmintic agent albendazole does not interact with P-glycoprotein. Drug Metabolism and Disposition, 30, 365–369
Merino, G., Molina, A.J., Garcia, J.L., Pulido, M.M., Prieto, J.G. and Alvarez, A.I., 2003. Intestinal elimination of albendazole sulfoxide: pharmacokinetic effects of inhibitors. International Journal of Pharmacology, 263, 123–132
Morani, P., Buronfosse, T., Longin-Sauvageon, C., Delatour, P. and Benoit, E., 1995. Chiral sulphoxidation of albendazole by the flavin adenine dinucleotide-containing and cytochrome P450-dependent mono-oxygenases from rat liver microsomes. Drug Metabolism and Disposition, 23, 160–165
Rabbaa, L., Dautrey, S., Colas-Linhart, N., Carbon, C. and Farinotti, R., 1996. Intestinal elimination of ofloxacin enantiomers in the rat: evidence of a carrier-mediated process. Antimicrobial Agents and Chemotherapy, 36, 2506–2511.
Rawden, H.L., Kokwaro, G.O., Ward, S.A. and Edwards, G., 2000. Relative contribution of cytochromes P450 and flavin-containing monooxygenases to the metabolism of albendazole by human liver microsomes. British Journal of Clinical Pharmacology. 49, 313–322
Redondo, P.A., Alvarez, A.I., Garcia, J.L., Larrode, O.M., Merino, G., and Prieto, J.G., 1999. resystemic metabolism of albendazole: experimental evidence of an efflux process of albendazole sulfoxide to intestinal lumen. Drug Metabolism and Disposition, 27, 736–740
Short, C.R., Barker, S.A. and Hsieh, L.C., 1987a. Disposition of fenbendazole in the goat. American Journal of Veterinary Research, 48, 811–815
Short, C.R., Barker, S.A. and Hsieh, L.C., 1987b. Disposition of fenbendazole in cattle. American Journal of Veterinary Research, 48, 958–961
Souhaili-El Amri, H., Mothe, O., Totos, M., Masson, C., Batt, A., Delatour, P. and Siest. G., 1988. Albendazole sulphonation by rat liver cytochrome P459c. Journal of Veterinary Pharmacology and Therapeutics, 246, 758–764
Strong, L., Wall, R., Woolford, A. and Djeddour, D., 1996. The effect of faecally excreted ivermectin and fenbendazole on the insect colonisation of cattle dung following the oral administration of sustained-release boluses. Veterinary Parasitology, 62, 253–266
Virkel, G., Lifschitz, A., Pis, A. and Lanusse, C., 2002. In vitro ruminal biotransformation of benzimidazole sulphoxide anthelmintics: enantioselective sulphoreduction in sheep and cattle. Journal of Veterinary Pharmacology and Therapeutics, 25, 15–13
Virkel, G., Lifschitz, A., Pis, A., Sallovitz, J. and Lanusse, C., 2004a. Comparative hepatic and extrahepatic enantioselective sulfoxidation of albendazole and fenbendazole in sheep and cattle. Drug Metabolism and Disposition, 32, 536–544
Virkel, G., Lifschitz, A., Sallovitz, J., Inza, G. and Lanusse, C., 2004b. Effect of the ionophore antibiotic monensin on the ruminal biotransformation of benzimidazole anthelmintics. The Veterinary Journal, 167, 265–271
Wall, R. and Strong, L., 1987. Environmental consequences of treating cattle with the antiparasitic drug ivermectin. Nature, 324, 418–420
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Gokbulut, C., Cirak, V.Y. & Senlik, B. Plasma Disposition and Faecal Excretion of Netobimin Metabolites and Enantiospecific Disposition of Albendazole Sulphoxide Produced in Ewes. Vet Res Commun 30, 791–805 (2006). https://doi.org/10.1007/s11259-006-3336-y
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DOI: https://doi.org/10.1007/s11259-006-3336-y