Disposition and metabolism of [14C]loperamide in rats

Abstract

Following oral administration of [14C]loperamide hydrochloride in 1 mg/kg to rats, plasma levels of radioactivity reached maximum at 4 hrs and decreased with a half-life of 4.1 hrs. Radioactivity in 96-hr feces accounted for 95% of the dose, with 30% associated with unchanged drug, while that in urine only 3.5%. Radioactivity in 48-hr bile accounted for 42% of the dose associated entirely with metabolites. 3% of the dose was found at the level of the enterohepatic cycles. These findings show that about 70% of the dose with absorbed by intestine, the target tissue of the drug, a portion (30%) of which was excreted back into intestinal cavity after demethylation, while the remaining 40% transferred to liver by which it was extracted mostly, metabolized extensively and excreted largely into bile, as supported by in vitro demethylating activity in gut segments but none in gut contents, and by in situ marked hepatic extraction of the drug. Main metabolic pathways involved are described.

P-Glycoprotein Increases Portal Bioavailability of Loperamide in Mouse by Reducing First-Pass Intestinal Metabolism

“…The kinetic parameters for transport and metabolism were generated from the in vitro studies with intestinal tissue of the same strains of mice, which enabled proper design and interpretation of the in vivo experiments Loperamide, a m-opioid receptor agonist that is used in the treatment of diarrhea, was chosen as a probe compound for this study because it has a low oral bioavailability (Heykants et al, 1974;Miyazaki et al, 1979) that is attributed to efficient P-gp-mediated efflux (Schinkel et al, 1996;Acharya et al, 2006) and extensive CYP3A-mediated first-pass metabolism (Kim et al, 2004). In fact, a quantitative measure of efficiency of P-gp [AQ, eq.…”

Prospective randomized double-blind trial of racecadotril compared with loperamide in elderly people with gastroenteritis living in nursing homes

“…The low efficacy of loperamide in our study could be related to a metabolic reaction due to drug interactions. Loperamide is mainly metabolized to desmethyl loperamide (DLOP) through the N-demethylation pathway [37,38], and clinical studies have shown that DLOP formed by LOP N-demethylation is a major metabolite of LOP in humans [39,40]. Moreover, it has been demonstrated that CYP2B6, CYP2C8, CYP2D6, and CYP3A4 catalyze LOP N-demethylation in human liver microsomes, and among them, CYP2C8 and CYP3A4 may play a crucial role in loperamide N-demethylation at therapeutic concentrations [41].…”

P-Glycoprotein-Based Loperamide–Cyclosporine Drug Interaction at the Rat Blood–Brain Barrier: Prediction from In Vitro Studies and Extrapolation to Humans

“…blood draw, the animal was sacrificed by decapitation and the brain harvested. This time point was chosen based on reported Lop pharmacokinetic studies in rats 16; 17 along with our pilot study in rats. Collectively, the literature and our pilot study results indicate that this duration was adequate for Lop and its metabolite, dLop, to reach pseudo-equilibrium between the brain and plasma, and exhibit linear pharmacokinetics at the Lop, dLop plasma concentrations studied 16; 17; 18 .…”