Hepatic and extra-hepatic metabolic pathways involved in flubendazole biotransformation in sheep

Abstract

Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound used in pigs, poultry and humans. Its potential for parasite control in ruminant species is under investigation. The objective of the work described here was to identify the main enzymatic pathways involved in the hepatic and extra-hepatic biotransformation of FLBZ in sheep. Microsomal and cytosolic fractions obtained from sheep liver and duodenal mucosa metabolised FLBZ into a reduced FLBZ metabolite (red-FLBZ). The keto-reduction of FLBZ led to the prevalent (approximately 98%) stereospecific formation of one enantiomeric form of red-FLBZ. The amounts of red-FLBZ formed in liver subcellular fractions were 3-4-fold higher (P<0.05) compared to those observed in duodenal subcellular fractions. This observation correlates with the higher (P<0.05) carbonyl reductase (CBR) activities measured in the liver compared to the duodenal mucosa. No metabolic conversion was observed following FLBZ or red-FLBZ incubation with sheep ruminal fluid. Sheep liver microsomes failed to convert red-FLBZ into FLBZ. However, this metabolic reaction occurred in liver microsomes prepared from phenobarbital-induced rats, which may indicate a cytochrome P450-mediated oxidation of red-FLBZ. A NADPH-dependent CBR is proposed as the main enzymatic system involved in the keto-reduction of FLBZ in sheep. CBR substrates such as menadione and mebendazole (a non-fluoride analogue of FLBZ), inhibited this liver microsomal enzymatic reaction, which may confirm the involvement of a CBR enzyme in FLBZ metabolism in sheep. This research is a further contribution to the understanding of the metabolic fate of a promissory alternative compound for antiparasitic control in ruminant species.

Chemoprophylactic Activity of Flubendazole in Cystic Echinococcosis

“…(3) Parent FLBZ is extensively metabolized into reduced and hydrolyzed metabolites in different species [16,[18][19][20] . (4) FLBZ formulation as cyclodextrin-based solutions increases its systemic bioavailability up to 25-fold in mice [16] .…”

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

“…Cytosolic ketone reductases were included in our study because a reduction of the carbonyl group gives rise to the main FLU metabolite (FLUR) in the first phase of biotransformation [14,18,31]. Moreover, aldo-keto reductases together with short-chain dehydrogenases/reductases regulate a wide range of physiological processes including reproduction, development and homeostasis.…”

“…Subcellular fractions obtained from sheep liver and duodenal mucosa metabolized FLU into a reduced FLU metabolite (FLUR). An NADPH-dependent carbonyl reductase (CBR) is proposed as the main enzymatic system involved in the keto-reduction of FLU in sheep [31]. Substrates of carbonyl reducing enzymes may act as their inducers as well [2,45], and is likely one of the mechanisms involved in CBR induction.…”

“…Until now, FLU has been prescribed only for swine and poultry, but the extension of its usage to small ruminants [31,33] (in oral suspension or with food as a premix) could be beneficial because of the broad spectrum of its anthelmintic activity. Additionally, FLU has a different biotransformation pattern in the host than other benzimidazoles due to the presence of carbonyl groups and absence of sulfur atoms in its molecule.…”

Transfer of flubendazole and tylosin from feed at cross-contamination levels to various poultry matrices

“…Livestock animals are exposed to a variety of veterinary drugs and feed additives. These compounds may be metabolized by different enzymatic systems of the hepatic and extrahepatic tissues (Maté et al, 2008). Biotransformation of benzimidazoles has been shown to be catalyzed by hepatic microsomal mixed-function oxidases; metabolic Transfer of flubendazole and tylosin from feed at cross-contamination levels to various poultry matrices V. Vandenberge ,* 1 E. Delezie , † P. Delahaut , ‡ G. Pierret , ‡ P. De Backer , § E. Daeseleire ,* and S. Croubels § reactions are sulfoxidation, demethylation, and hydroxylation (Moreno et al, 2004).…”