Gastrointestinal distribution of the prodrug loperamide oxide and its active drug loperamide in the dog.

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.

Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.

Risperidone is a new benzisoxazole antipsychotic. 9-Hydroxy-risperidone is the major plasma metabolite of risperidone. The pharmacological properties of 9-hydroxy-risperidone were studied and appeared to be comparable to those of risperidone itself, both in respect of the profile of interactions with various neurotransmitters and its potency, activity, and onset and duration of action. The absorption, plasma levels and regional brain distribution of risperidone, metabolically formed 9-hydroxy-risperidone and total radioactivity were studied in the male Wistar rat after single subcutaneous administration of radiolabelled risperidone at 0.02 mg/kg. Concentrations were determined by HPLC separation, and off-line determination of the radioactivity with liquid scintillation counting. Risperidone was well absorbed. Maximum plasma concentrations were reached at 0.5-1 h after subcutaneous administration. Plasma concentrations of 9-hydroxy-risperidone were higher than those of risperidone from 2h after dosing. In plasma, the apparent elimination half-life of risperidone was 1.0 h, and mean residence times were 1.5 h for risperidone and 2.5 h for its 9-hydroxy metabolite. Plasma levels of the radioactivity increased dose proportionally between 0.02 and 1.3 mg/kg. Risperidone was rapidly distributed to brain tissues. The elimination of the radioactivity from the frontal cortex and striatum--brain regions with high concentrations of 5-HT2 or dopamine-D2 receptors--became more gradual with decreasing dose levels. After a subcutaneous dose of 0.02 mg/kg, the ED50 for central 5-HT2 antagonism in male rats, half-lives in frontal cortex and striatum were 3-4 h for risperidone, whereas mean residence times were 4-6 h for risperidone and about 12 h for 9-hydroxy-risperidone. These half-lives and mean residence times were 3-5 times longer than in plasma and in cerebellum, a region with very low concentrations of 5-HT2 and D2 receptors. Frontal cortex and striatum to plasma concentration ratios increased during the experiment. The distribution of 9-hydroxy-risperidone to the different brain regions, including frontal cortex and striatum, was more limited than that of risperidone itself. This indicated that 9-hydroxy-risperidone contributes to the in vivo activity of risperidone, but to a smaller extent than would be predicted from plasma levels. AUCs of both active compounds in frontal cortex and striatum were 10-18 times higher than those in cerebellum. No retention of metabolites other than 9-hydroxy-risperidone was observed in any of the brain regions investigated.