Sustained treatment with fenbendazole induces cytochrome P450 enzyme activities in swine

Abstract

The anthelmintic fenbendazole (FBZ), a benzymidazole (BZD) drug, is used to control gastrointestinal parasites in swine production. This compound is commercially available as a powder to be mixed with food for oral administration in pigs for 7-10 days. BZD-containing drugs possess the ability to significantly induce certain cytochrome P450 (CYP) isozymes in different species, particularly those belonging to the CYP1A family. This work aimed to evaluate in vitro the effect FBZ sustained administration on CYP1A-dependent enzyme activities in pig liver. Eleven (11) piglets were divided in two groups: five (5) animals remained untreated and used as controls; six (6) animals were treated with a FBZ commercial powder mixed with food. The drug concentration in food was 0.01% and animals were fed ad libitum for 10 days. Animals were euthanized for preparation of liver microsomes. Two CYP 1A-dependent enzyme activities, namely 7-ethoxuresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) were assayed in a spectrofluorometer. FBZ and its S-oxygenated metabolites, oxfendazole (OFZ) and fenbendazole sulphone (FBZSO2), were detected in the systemic circulation of treated piglets. Mean plasma AUCs (µg.day/mL) were 0.28±0.08 (FBZ), 4.10±0.58 (OFZ) and 4.56±1.01 (FBZSO2). The parent drug FBZ represented around the 46% (4.66±1.59 µg/g) of the total anthelmintic molecules in the liver, followed by OFZ (3.11±1.06 µg/g, 31%) and the inactive FBZSO2 (2.30±0.99 µg/mL, 23%). In liver microsomes from treated animals, both EROD and MROD enzyme activities increased 24.5-fold (p=0.003) and 17.2-fold (p=0.0006), respectively. The sustained administration of FBZ caused the induction of the CYP1A-dependent metabolism in pig liver. This fact may affect the metabolic fate of FBZ itself but also of other foreign compounds such as aflatoxin B1 present in certain pig foodstuffs.