title: Disposition of zatosetron, a serotonin (5-HT3) receptor antagonist, in humans.
abstract: Zatosetron is being tested clinically as an antianxiety agent; it is a highly selective antagonist of the serotonin 5-HT3 receptor, with minimal agonist activity. The disposition of [14C]zatosetron was studied in five healthy men after a single oral dose (46.2 mg). Serum levels of radioactivity and parent drug peaked in 3-8 hr. About 15% more radioactivity was measured in red blood cells than in plasma. In serum, the parent compound represented about 85% of the radioactivity, zatosetron-N-oxide represented 10%, and N-desmethyl-zatosetron and 3-hydroxy-zatosetron each represented 2-3%. The t1/2 of zatosetron was 25-37 hr. About 75% of zatosetron added to human plasma became reversibly bound to protein. Concentrations of zatosetron in saliva were generally 10-50% higher than those in serum. About 80% of the administered radioactivity was eliminated in urine and 20% in feces; radioactivity was measurable in the excreta for 10-12 days after drug administration. The major route of metabolism of zatosetron was a stereoselective N-oxidation to form 8-alpha-methyl, 8-beta-oxo zatosetron (zatosetron N-oxide). In urine, approximately 45% of the radioactivity was unchanged zatosetron, 35% was zatosetron N-oxide, 10% was N-desmethyl-zatosetron, and 5% was 3-hydroxy-zatosetron. In feces, 30% of the radioactivity was unchanged zatosetron, and 70% was N-desmethyl-zatosetron. Overall, approximately 60% of the administered zatosetron was metabolized in humans. In a separate multiple-dose study, the disposition of zatosetron was found to be similar to that in the single-dose study.
authors.affiliation: Lilly Laboratory for Clinical Research, Eli Lilly and Company, Indianapolis, IN 46202.
authors.forename: P M
authors.initials: PM
authors.lastname: Franz
authors.forename: E L
authors.initials: EL
authors.lastname: Mattiuz
authors.forename: B L
authors.initials: BL
authors.lastname: Hatcher
authors.forename: K A
authors.initials: KA
authors.lastname: DeSante
authors.forename: A P
authors.initials: AP
authors.lastname: Breau
authors.forename: J L
authors.initials: JL
authors.lastname: Occolowitz
authors.forename: D E
authors.initials: DE
authors.lastname: Dorman
authors.forename: C R
authors.initials: CR
authors.lastname: Schmid
authors.forename: M J
authors.initials: MJ
authors.lastname: Goldberg
authors.forename: A
authors.initials: A
authors.lastname: Rubin
mesh_terms: D000328:Adult; D001572:Benzofurans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002851:Chromatography, High Pressure Liquid; D003640:Dealkylation; D005243:Feces / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D011485:Protein Binding; D012463:Saliva / Q000378:metabolism; D012702:Serotonin Antagonists
chemical_list: D001572:Benzofurans; D001798:Blood Proteins; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D012702:Serotonin Antagonists; C064877:zatosetron