In vitro inhibition of the hepatic S-oxygenation of the anthelmintic albendazole by the natural monoterpene thymol in sheep

Combinations of bioactive phytochemicals with synthetic compounds have been suggested as promissory tools for the improvement of nematode control in livestock. Bioactive phytochemicals may interfere with the activity of drug-metabolizing enzymes and delay the metabolic conversion of anthelmintics into less potent metabolites. This research assessed the effect of the monoterpene thymol (TML) on the in vitro hepatic metabolism of the anthelmintic albendazole (ABZ) in sheep. Liver microsomes from four (4) Texel lambs were incubated with ABZ (50 mu M) in absence or in presence of TML (0.05-10 mM). The concentration of TML producing a 50% decrease in ABZ S-oxygenation (IC50) was 13.5 mM. The FMO-dependent S-oxygenation of ABZ was markedly inhibited by the monoterpene (54.1 +/- 11.6%, p < .01). In agreement with this observation, TML produced a marked inhibition of benzydamine (BZ) N-oxidase, a specific FMO activity. The CYP-dependent production of the sulfoxide metabolite (ABZSO) was less affected, being 25.3 +/- 17.5 lower (p < .05) in presence of TML. Additionally, TML completely abolished the specific CYP1A1-dependent enzyme activity 7-ethoxyresorufin O-deethylase. Overall, the results presented here show that, in addition to its own anthelmintic affect, TML may potentiate ABZ anthelmintic activity by preventing its metabolic conversion into a less active metabolite.