Antidiarrheal specificity and safety of the n‐oxide of loperamide (R 58 425) in rats

Abstract

Neimegeers, C.J.E., F. Awouters, F.M. Lenaerts, K.S.K. Artois, and J. Vermeire: Antidiarrheal specificity and safety of the N-oxide of loperamide (R 58 425) in rats. Drug Dev. Res. 8:279-286, 1986.The pharmacological and toxicological effects of loperamide and the N-oxide of loperamide were studied in adult and 19-day-old rats and in I-day-old pups. In adult rats both orally administered compounds were equipotent and specific antidiarrheals, but the N-oxide was slightly less toxic. In these rats, i.v. injected N-oxide, in contrast to loperamide, did not induce opiate-like central effects and its intestinal activity developed more gradually. In 19-day-old rats high oral doses of both compounds induced opiate-like behavioral effects, but the i.v. injected N-oxide was again virtually devoid of these effects and proved 5 times less toxic than i.v. loperamide. The orally administered compounds in 1-day-old pups induced lethality at doses slightly higher than the i.v. lethal doses of loperamide in 19-day-old and adult rats. The results are in agreement with rapid and efficient conversion of the N-oxide to loperamide in intestine and in liver, and a much slower and pharmacologically hardly detectable conversion of circulating N-oxide. The visceral barriers, which limit access of the orally administered compounds to the systemic circulation, appear fully developed in 19-day-old rats; the blood-brain barrier at this age is still more permeable than in adult rats. The more gradual development of antidiarrheal activity and the reduced risk of acute systemic intoxication are the major pharmacological differences between orally administered N-oxide and loperamide.

Increased systemic availability of loperamide after oral administration of loperamide and loperamide oxide with cotrimoxazole

“…Loperamide oxide, a pro-drug of loperamide, is significantly less active in the guinea pig ileum in vitro than loperamide, having only half the binding affinity for p-opiate-receptors of loperamide [ Janssen Research Foundation; on file]. In contrast loperamide and its oxide are equipotent in vivo [3], supporting the hypothesis that the efficacy of loperamide oxide in vivo is brought about by its conversion to loperamide within the gut [4].…”

Antisecretory Activities of Orally Administered Loperamide and Loperamide Oxide on Intestinal Secretion in Rats

“…In an effort to make loperamide even safer, a pharmacologically inactive prodrug of loperamide, loperamide oxide, was synthesized. The antidiarrhoeal effect of loperamide oxide was attributed to the conversion of loperamide oxide to loperamide in the gastrointestinal tract (Niemegeers et al 1986;Goldhill et a1 1989). The reduction of loperamide oxide to loperamide by intestinal contents, red blood cells and liver microsomes has been demonstrated in-vitro (Lavrijsen et al 1984).…”

The effect of loperamide oxide on prostaglandin-stimulated fluid transport in rat small intestine

“…To overcome this problem, the N-oxide, loperamide oxide, a pro-drug of loperamide, has been developed. N-Oxides of alkaloids have previously been shown to be inactive (Bickel 1969), but oral administration of loperamide oxide inhibited caster oil-induced diarrhoea (Niemegeers et al 1986). This effect was attributed to the conversion of loperamide oxide to loperamide in the gastrointestinal tract since following oral administration of loperamide oxide, the parent drug loperamide appeared in the blood (Monbaliu et al 1984).…”