Metabolites of loperamide in rats

Abstract

Following intraperitoneal administration to rats of [14C]loperamide, [carbonyl-14] 4-(p-chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha, alpha-diphenyl-1-piperidine butyramide, metabolites in feces and urine were separated, and identified by means of mass spectrometry. In feces, six metabolites were identified in addition to the unchanged drug. The main metabolic pathways involved are dealkylation in the dimethyl amide moiety to give desmethyl- and didesmethylloperamide, both of which were in turn monohydroxylated either in the alpha-phenyl ring or possibly in the alpha-carbon in the piperidine ring. It is noteworthy that metabolites hydroxylated in the piperidine ring were isolated as pyridinium derivatives, possibly due to spontaneous aromatization of its 2,4-dihydroxy-4-(p-chlorophenyl)piperidine ring. In urine, only two metabolites were found and identified to be desmethyl- and didesmethylloperamide, since [14C]loperamide was excreted into urine only in a small amount.

Disposition and metabolism of [14C]loperamide in rats

“…An investigation of these problems was therefore made, using [l4C]loperamide labeled at the carbonyl carbon. The extensive metabolism of loperamide observed has been reported in a previous paper (7) while the present paper describes the disposition of [l4C]loperamide in rats and gives additional metabolic data.…”

“…Fecal homogenate and urine were fractionated into basic and acidic fractions by shaking with chloroform at an alkaline and then at an acidic pH and the remainder was considered the polar fraction, as described in a previous paper (7). The polar fraction of urine was adjusted to pH 6.8 with phosphate buffer, and incubated at 3"JOC for 16 hrs with bacterial type-I (3-glucuronidase (Sigma Chemicals Co., Ltd., St. Louis, U.S.A.): the enzyme treatment was confirmed to be sufficient for complete hydrolysis.…”

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].…”

11C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux

“…For example, despite high doses and high plasma concentrations in human subjects, loperamide almost completely lacks central nervous system effects, because P-gp efficiently blocks virtually all uptake by the brain. Loperamide is rapidly metabolized in mammals mainly by dealkylation of the dimethyl amide moiety (12,13). Some metabolites of loperamide, including N-desmethyl-loperamide (N-dLop), are predicted to have adequate lipophilicity to enter the brain if not inhibited by P-gp.…”