GASTROINTESTINAL DISTRIBUTION OF THE PRODRUG LOPERAMIDE OXIDE AND ITSACTIVE-DRUG LOPERAMIDE IN THE DOG

Loperamide oxide is a prodrug of the effective antidiarrheal loperamid e. Administration of this prodrug improves efficacy and tolerability. For better understanding of these effects, the absorption and gastroin testinal distribution of loperamide oxide and of its active drug loper amide were studied. Beagle dogs received a single oral dose of loperam ide oxide or loperamide at 0.16 mg/kg. Plasma, gastrointestinal conten ts and tissues, and some other organs were obtained. Concentrations we re determined by specific radioimmunoassays. Loperamide oxide was grad ually converted to loperamide in the gastrointestinal tract. After adm inistration of the prodrug, the systemic absorption of the active drug was lower and more delayed than after administration of loperamide it self. As a consequence, more loperamide was available in the contents and the mucosa of the gut, in particular in the lower part of the smal l intestine and in the large intestine. The higher revels of loperamid e 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-releas e form of loperamide keeping a higher amount of the active drug for a longer time at the site of action in the gut wall.