Pharmacokinetics and metabolism of the 5-hydroxytryptamine antagonist tropisetron after single oral doses in humans.

Tropiestron is a potent and selective antagonist of 5-hydroxytryptamine receptors. Tropisetron was developed for the indication of cancer chemotherapy-induced emesis. The pharmacokinetic and metabolic dispositions of tropisetron were studied in 12 healthy male volunteers receiving a single oral dose of 62 or 312 mumol (20 or 100 mg) of [14C]tropisetron. Serial plasma samples and complete urine and feces were collected for 120 hr postdose. Whereas the absorption of oral doses of 62-312 mumol tropisetron was rapid and complete, bioavailability was estimated to be only 66% for the 312 mumol dose and 52% for the 62 mumol dose, apparently because of saturable first-pass metabolism. Maximal concentrations of tropisetron averaged 87 and 608 nM after doses of 62 and 312 mumol, respectively, and the parent drug accounted for 21 and 36% of the radioactivity in AUC0-24 hr pools. Approximately 90% of the drug was metabolized before excretion, and approximately 70% of the dose was recovered in the urine. Following both the 62 and 312 mumol doses, the terminal half-life of tropisetron averaged 6-7 hr and that of total radioactivity was 10-11 hr. Tropisetron and its metabolites in plasma and urine were separated by gradient elution reversed-phase HPLC. Structures of eight metabolites were assigned on the bases of NMR and MS data. Tropisetron was metabolized by oxidative hydroxylation of the indole ring at positions 5, 6, and 7. The hydroxylated derivatives are further conjugated with glucuronic acid and sulfate. N-Oxygenation and oxidative N-demethylation at the tropinyl nitrogen also occur in trace amounts.(ABSTRACT TRUNCATED AT 250 WORDS)