METABOLISM AND DISPOSITION OF C-14 GRANISETRON IN RAT, DOG AND MAN AFTER INTRAVENOUS AND ORAL DOSING

1. The disposition and metabolic fate of C-14-granisetron, a novel 5-H T3 antagonist, was studied in rat, dog, and male human volunteers afte r intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailab ility was reduced by first-pass metabolism in all three species. 3. Th ere were no sex-specific differences observed in radiometabolite patte rns in rat or dog and there was no appreciable change in disposition w ith dose between 0.25 and 5 mg/kg in rat and 0.25 and 10 mg/kg in dog. Additionally, there were no large differences in disposition associat ed with route of administration in rat, dog and man. 4. In rat and dog , 35-41% of the dose was excreted in urine and 52-62% in faeces, via t he bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, ab out 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was onl y excreted in urine (5-25% of dose). 5. The major metabolites were iso lated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing wer e 5-hydroxylation and N1-demethylation, followed by the formation of c onjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with le sser quantities of the 6,7-dihydrodiol and/or their conjugates.