Antisecretory activities of orally administered loperamide and loperamide oxide on intestinal secretion in rats.

In-vivo experiments in the rat jejunum have been performed to compare the antisecretory effect of orally administered loperamide with the effect of its pro-drug, loperamide oxide. Both loperamide and loperamide oxide, administered orally, reduced the secretory effect of prostaglandin E2 (32 ng min-1, intra-arterially) in the jejunum and the colon. Differences between the two drugs as to time course and dose response can be seen. Loperamide oxide shows its antisecretory effect in the jejunum, and at a dose of 2 mg kg-1 also shows its effect in the colon 1 h after administration. The effect was maximal after 2 h and decreased after 4 h. A dose-response relationship was demonstrated at 2 h in the jejunum and the colon. In comparison, the effect of loperamide started later, and a good dose-response relationship was not observed in the jejunum or in the colon, higher doses always appearing less effective than lower doses.

5-HT receptor antagonists and heat-stable Escherichia coli enterotoxin-induced effects in the rat.

The effect of heat-stable E. coli enterotoxin on intestinal fluid secretion is commonly considered to be mediated by stimulation of mucosal cyclic guanosine monophosphate (cGMP). It was demonstrated recently that 5-hydroxytryptamine (5-HT) acts as an important mediator in cholera toxin-induced fluid secretion. To elucidate the possible involvement of 5-HT in the secretory response to heat-stable E. coli enterotoxin, in vivo experiments were performed in the rat jejunum. The inhibitory effects of the 5-HT2 receptor antagonist ketanserin, the 5-HT3 receptor antagonist tropisetron and indomethacin were studied in heat-stable E. coli enterotoxin-induced fluid secretion. Tropisetron and ketanserin (100 micrograms/kg each) alone only partially reduced the secretory effect of the toxin. However, in combination, the two blockers (100 plus 100 micrograms/kg) significantly reduced and at 200 plus 200 micrograms/kg totally abolished heat-stable E. coli enterotoxin-induced secretion without influencing the enterotoxin-induced increase in cGMP. Pretreatment with indomethacin (10 mg/kg) reduced the secretory response to the enterotoxin by about 50%. These results support the concept that 5-HT is an important mediator in intestinal fluid secretion induced by heat-stable E. coli enterotoxin. The enterotoxin may use 5-HT to stimulate prostaglandin formation via 5-HT2 receptors and to activate neuronal structures via 5-HT3 receptors.

Comparison of the antisecretory effects of loperamide and loperamide oxide in the jejunum and the colon of rats in-vivo.

The antidiarrhoeal effect of loperamide is caused by its antimotility and antisecretory properties. In-vivo experiments in the rat jejunum and colon have been performed to compare the antisecretory effect of loperamide with the effect of its prodrug, loperamide oxide. Both loperamide and loperamide oxide administered intraluminally, equally and dose dependently (2 to 250 micrograms mL-1) reduced PGE2-induced net fluid secretion (32 ng min-1 i.a.) in the jejunum and colon. The antisecretory effect of both drugs is blocked by naloxone (1 mg kg-1 s.c.). It is concluded that loperamide oxide administered intraluminally is reduced to loperamide and has the same antisecretory potency as loperamide in jejunum and colon. The effect appears to be mediated via opiate receptors. The observation that loperamide cannot be detected in the colonic lumen two h after oral administration suggests that the drug is delivered from the blood stream to the site of action after absorption in the small intestine.