Pharmacokinetics and tolerability of ascending intravenous doses of granisetron,a novel 5-HT3 antagonist,in healthy human subjects

The pharmacokinetics and tolerance of granisetron, a novel 5HT₃-receptor antagonist which is under development as an anti-emetic agent have been studied after administration of single 30 min intravenous infusions to three groups of 8 healthy male subjects, in a series of placebo-controlled ascending dose studies (50, 80, 100 and 130 g·kg^–1 to group 1; 150, 180, 200 and 230 g·kg^–1 to group 2 and 270 and 300 g·kg^–1 to group 3). Plasma and urine samples were analysed for granisetron by HPLC with fluorimetric detection.Administration of granisetron was well tolerated by the volunteers and there were no serious adverse effects reported. Pharmacokinetic parameters and dose-normalised plasma levels appeared to be independent of dose in the range 50 to 300 g·kg^–1, although there was extensive inter-subject variability. Granisetron was extensively distributed, with mean volumes of distribution ranging from 186–264 l at the various doses. Total plasma clearance was, in general, rapid (mean values of 37.0 to 49.9 l·h^–1) and predominantly non-renal, with most subjects excreting less than 20% of the dose unchanged in urine. Mean t_1/2 values ranged from 4.1 to 6.3 h and MRT from 5.2 to 8.1 h.