Intestinal elimination of albendazole sulfoxide: pharmacokinetic effects of inhibitors.

Albendazole (ABZ) is an anthelmintic drug widely used in human and veterinary medicine. Intestinal and hepatic ABZ metabolism leads to albendazole sulfoxide (ABZSO), the active metabolite. This work examines the mechanism involved in intestinal elimination of ABZSO and their pharmacokinetic consequences in rat and sheep. To assess the drug intestinal elimination, an upper small intestine segment was isolated and perfused in situ with saline, after ABZSO administration (10 mg/kg i.v.). The intestinal clearance of ABZSO was 0.106+/-0.010 ml/min, exhibiting a stereoselective intestinal elimination to (-)ABZSO form. Oxfendazole, ampicillin and cyclosporine significantly reduced the intestinal elimination of ABZSO to 0.079+/-0.008, 0.069+/-0.009 and 0.065+/-0.012 ml/min, respectively. Glucose significantly induced ABZSO intestinal elimination. Pharmacokinetic results showed a clear and statistically significant interaction between ABZ metabolites and drug efflux inhibitors. In rat, an increased area under the curve (AUC) for ABZSO in the groups co-administered with ABZ plus verapamil (43%) and plus ketoconazole (29%) was obtained. In sheep, the AUC for ABZSO in the groups co-administered with the inhibitors were significantly higher 53.68% with verapamil, 78.62% with quinidine, and 50.55% with ivermectin.