ABSTRACT:The enantioselective sulfoxidation of the prochiral anthelmintic compounds albendazole (ABZ) and fenbendazole (FBZ) was investigated in liver, lung and small intestinal microsomes obtained from healthy sheep and cattle. The microsomal fractions were incubated with a 40 M concentration of either ABZ or FBZ. Inhibition of the flavin-containing monooxygenase (FMO) system was carried out by preincubation with 100 M methimazole (MTZ) either with or without heat pretreatment (2 min at 50°C). ABZ and FBZ were metabolized to the (؉) and (؊) enantiomers of their sulfoxide metabolites, named albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively. ABZ sulfoxidation rates were higher (p < 0.001) than those observed for FBZ. The FMO-mediated liver sulfoxidation of ABZ was enantioselective (100%) toward the (؉) ABZSO production in both species. Liver sulfoxidation of FBZ by FMO was also enantioselective toward (؉) OFZ (sheep ؍ 65%; cattle ؍ 79%). Cytochrome P450 was found to be mainly involved in the production of (؊) ABZSO in the liver. MTZ did not affect the sulfoxidation of ABZ by lung microsomes, which may indicate that FMO is not involved in the production of ABZSO in this tissue. A significant (p < 0.05) inhibition of (؊) ABZSO production by liver microsomes was observed after ABZ incubation in the presence of erythromycin (cattle ؍ 21%) and ketoconazole (sheep ؍ 36%). Both CYP3A substrates induced a reduction in the production of (؊) ABZSO (sheep ؍ 67-78%, cattle ؍ 50-78%) by lung microsomes. Overall, the results reported here contribute to the identification of the metabolic pathways involved in the biotransformation of benzimidazole anthelmintics extensively used for parasite control in ruminants.Livestock animals are exposed to a variety of xenobiotic agents (i.e., veterinary drugs, feed-additives, pesticides, pollutants, etc.) during their production cycles. These compounds are likely to be metabolized by different enzymatic systems from both hepatic and extrahepatic tissues. The metabolic activity of the flavin-containing monooxygenase (FMO) and cytochrome P450 (P450) systems plays a major role in determining the persistence of therapeutically used drugs in target species, which may additionally impose a risk to the consumer as a consequence of the permanence of drug residue levels in edible tissues. Metabolic interactions with either the FMO or P450 enzymatic systems may drastically affect the disposition kinetics of different drugs used in animal production, which will have a relevant impact on the pattern of drug/metabolite residues in edible tissues, a major concern for public health and consumer safety.Benzimidazole (BZD 1 ) and pro-BZD anthelmintics are extensively metabolized in domestic animals and humans. Their metabolic pattern and the resultant pharmacokinetic behavior are relevant in the attainment of high and sustained concentrations of pharmacologically active drug/metabolites at the target parasite . Albendazole (ABZ; methyl-[(5-propylthio)-1H-benzimidazol-2-yl] carba...