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

The pharmacological and toxicological effects of loperamide and the N‐oxide of loperamide were studied in adult and 19‐day‐old rats and in 1‐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.