Inhibitory actions of loperamide on absorptive processes in rat small intestine.

Abstract

SUMMARY Mucosal loperamide caused a dose dependent reduction in the absorption of actively transported hexoses and amino acids, together with the associated rise in short circuit current. Na+ and fluid movement were also inhibited. Serosal application of the drug was without effect on these processes. The passive movement of fructose across the gut was not affected by loperamide which is therefore unlikely to act by reducing tissue permeability. In low Na+ conditions the inhibitory actions of loperamide on glycine absorption were reduced. Loperamide reduced basal Na+ transport although it did not affect the stimulation of Na+ absorption caused by mannose. Loperamide had no effect on the total ATPase activity nor on the Na+, K+-ATPase activity of mucosal homogenates. The effects of loperamide were not mimicked by morphine nor were they antagonised by naloxone and hence do not seem to involve an opiate receptor. It is concluded that loperamide exerts its inhibitory effects by an interaction with the Na+ sites of the nutrient carriers.Loperamide (Imodium, Janssen) is an opiate agonist which is used as an antidiarrhoeal agent.' Its therapeutic efficacy appears to arise not only from an action on the motor functions of the intestine, which results in slowed intestinal transit and increased gut capacitance,2 but also from its ability to inhibit intestinal secretion.3 6The antisecretory actions of loperamide are observed in response to serosal application of the drug. Loperamide is, however, administered orally and will therefore come into contact with the luminal surface of the intestinal epithelium, which is the site of absorptive processes in the intestine. The present investigation indicates that loperamide causes an inhibition of hexose and amino acid absorption and the associated movement of Na+ and fluid in everted sacs of rat small intestine. Methods RATSExperiments were carried out on male albino rats weighing between 230 and 250 g. These were allowed free access to food (diet 86, Oxoid, London) and water. They were anaesthetised with sodium pentobarbitone (60 mg/kg ip).

Loperamide Inhibits the Enhanced Intestinal Glucose Absorption of Cystic Fibrosis In Vitro

“…The ability of loperamide to inhibit intestinal absorption has been established with tissue from the rat (13). Loperamide in the mucosal solution was found to reduce the Na'-linked absorption of nutrients determined both directly and as an increase in transintestinal electrical activity.…”

“…The antidiarrheal agent loperamide inhibits Na+-linked nutrient absorption in rat small intestine, (13) and the aim of the 3 present study was to determine whether this agent could reduce the enhanced absorption in the CF bowel.…”

Effect of Loperamide on Na+/d-Glucose Cotransporter Activity in Mouse Small Intestine

“…However, in comparison with its antidiarrhoeal action, the inhibition of glucose uptake by loperamide occurred at relatively high concentrations; we calculated an IC50 value of 450 mmol L À1 . This IC50 value is in the same range as that inhibiting Na -dependent amino acid absorption in intact rat intestine (Hardcastle et al 1986). Stoll et al (1988) were unable to demonstrate an inhibitory effect of loperamide on Na -dependent glucose transport in human ileal BBMV.…”

“…Loperamide also inhibits intestinal absorptive processes (Chang et al 1986;Balkovetz et al 1987;Stoll et al 1987Stoll et al , 1988, and it has been shown to reduce the Na -dependent uptake of glucose and other nutrients in both intact rat small intestine and biopsies from human jejunum in-vitro (Hardcastle et al 1986(Hardcastle et al , 1994. The effects of loperamide on intestinal absorptive processes have been reported to be mediated through an inhibition of calmodulin activity (Zavecz et al 1982;Diener et al 1988;Stoll et al 1988;Okhuysen et al 1995) and, in addition, an intracellular site of interaction of the drug with transporter proteins has been proposed (Stoll et al 1988).…”

Pharmacological treatment of the biochemical defect in cystic fibrosis airways

“…Loperamide, an opiod receptor agonist, inhibited sodium ion flux in the rat small bowel in vitro [62]. Although loperamide reduced NPD in CF mouse nasal epithelium in vivo [63], preliminary data in humans show that loperamide is less potent than amiloride in inhibiting NPD in CF suggesting that it is unlikely to be clinically useful [64].…”