Sustained Treatment With Fenbendazole in Swine: Plasma Availability and Effects on Xenobiotic Metabolizing Enzymes in the Liver

Abstract

Abstract Fenbendazole (FBZ), a benzymidazole (BZD) anthelmintic drug, is used for in-feed medication in pigs. BZD-containing drugs may induce cytochrome P450 isozymes (CYPs), particularly those members of the CYP1A subfamily. This research aimed to evaluate in vitro the effect of the in vivo sustained administration of FBZ on the catalytic activities of xenobiotic metabolizing enzymes in pig liver. The availability of FBZ and its metabolites in plasma and liver tissue was also assessed. Five Landrace piglets remained untreated (controls), and other six were treated with a pre-mix of FBZ, combined with food, for 9 consecutive days as usually is recommended by practitioners. Blood samples were collected from each treated animal up to day 9 and analyzed by HPLC; both control and treated animals were slaughtered for preparation of liver microsomes. Plasma concentration ratios OFZ/FBZ and FBZSO2/OFZ increased significantly (p<0.05) from the beginning to the end of drug exposure, which may indicate an enhanced conversion of FBZ into its metabolites. FBZ represented 45.8±3.4% of the total anthelmintic molecules in liver tissue. Increased CYP1A-dependent 7-ethoxy (24.5-fold, p=0.0032) and 7-methoxyresorufin (17.2-fold, p=0.0006) O-dealkylase activities was observed in liver microsomes from FBZ-treated animals. The continuous FBZ administration may accelerate its own in vivo hepatic metabolism through the CYP1A pathway, which may have a negative impact on its clinical efficacy. CYP1A induction in pig liver may also affect the biotransformation of other xenobiotics such as aflatoxin B1 present in certain pig foodstuffs.