title: [Analysis of 5-HT3 receptor antagonist, ramosetron hydrochloride, based on receptor occupancy considering its active metabolite].
abstract: Severe nausea and vomiting induced by antineoplastics diminish the patient's quality of life and the ability to tolerate further chemotherapy. Ramosetron hydrochloride is a 5-HT3 receptor antagonist, which has an active metabolite (M-1), expected to be useful in the inhibition of chemotherapy-induced nausea and vomiting. In the present study, in order to analyze the pharmacological effect of ramosetron hydrochloride in a comprehensive manner, we estimated the 5-HT3 receptor occupancy after intravenous administration of ramosetron hydrochloride using pharmacokinetic parameters and the dissociation constants for the 5-HT3 receptor. The average total receptor occupancy after intravenous administration of 0.3 mg of ramosetron hydrochloride to human was calculated to be 82.9% (ramosetron, 77.8%; M-1, 5.1%), thus exhibiting a significant antiemetic activity. Furthermore, the estimated time course of 5-HT3 receptor occupancies after intravenous administration of 0.3 mg of ramosetron hydrochloride suggested a substantial impact of the active metabolite (M-1). It suggested that M-1 contributed to the long duration of binding on the 5-HT3 receptor. The present analysis method should be useful for designing the rational dosage regimen of ramosetron hydrochloride and predicting the duration of its antiemetic activity in a quantitative manner.
authors.affiliation: Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ogata
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Sugiura
authors.forename: R
authors.initials: R
authors.lastname: Takayanagi
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: T
authors.initials: T
authors.lastname: Iga
mesh_terms: D001562:Benzimidazoles / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D006801:Humans; D007275:Injections, Intravenous; D008954:Models, Biological; D011985:Receptors, Serotonin / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D001562:Benzimidazoles; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C071315:ramosetron