Metabolism and disposition of¹⁴C-granisetron in rat, dog and man after intravenous and oral dosing

Abstract

1. The disposition and metabolic fate of 14C-granisetron, a novel 5-HT3 antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration. 2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species. 3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with 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 associated 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 the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5-25% of dose). 5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…74). It undergoes hydroxylation on the indazole ring at the 7-position (Clarke et al, 1994) to yield a metabolite with slightly greater target potency than the parent drug (Vernekar et al, 2010). After both oral and intravenous administration, the metabolite is present at about 10% of that of the parent (Clarke et al, 1994;Boppana, 1995).…”

The pharmacokinetics of granisetron, a 5-HT3 antagonist in healthy young and elderly volunteers

“…Differences in protein binding of granisetron between young and elderly are unlikely to be a significant factor, since this drug is only moderately protein bound (circa 65 %; A. Allen, unpublished data) even in young, healthy individuals. The lower total plasma clearance of granisetron in the elderly may be the result of an age-related reduction in its oxidative metabolism, 7-hydroxylation by a 3A family P450 representing its major route of elimination [10,11]. Reductions in oxidative status in the elderly have been well documented [12,13].…”

Ondansetron and Granisetron in Prophylaxis of Nausea and Emesis Inducedby Cisplatin in Dogs

“…In these studies, granisetron was used in different dosages with different aims. It was administered intravenously (0.316 mg/kg) for determination of plasma peptide YY levels with cisplatininduced emesis in dogs (Perry et al1994); administered intravenously (0.5 mg/kg) for comparison of antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-induced emesis in dogs (Sharma et al 1997); administered intravenously (0,25 -10 mg/kg) to investigate, the disposition and metabolic fate of granisetron had studied in rats, dogs, and male human volunteer (Clarke et al 1994). But, these dosages were higher (almost 10 -200 times) than doses in humans for prophylaxis regimens of nausea and vomiting induced by cisplatin.…”