Abstract

Loperamide oxide is a prodrug of the effective antidiarrheal loperamide. Administration of this prodrug improves efficacy and tolerability. For better understanding of these effects, the absorption and gastrointestinal distribution of loperamide oxide and of its active drug loperamide were studied. Beagle dogs received a single oral dose of loperamide oxide or loperamide at 0.16 mg/kg. Plasma, gastrointestinal contents and tissues, and some other organs were obtained. Concentrations were determined by specific radioimmunoassays. Loperamide oxide was gradually converted to loperamide in the gastrointestinal tract. After administration of the prodrug, the systemic absorption of the active drug was lower and more delayed than after administration of loperamide itself. As a consequence, more loperamide was available in the contents and the mucosa of the gut, in particular in the lower part of the small intestine and in the large intestine. The higher levels of loperamide in mucosa may cause more pronounced and longer lasting antisecretory effects after administration of loperamide oxide. The results of this study are in line with the hypothesis that loperamide oxide is a site-specific prodrug that acts as a chemically designed controlled-release form of loperamide keeping a higher amount of the active drug for a longer time at the site of action in the gut wall.