[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: A Ogata, Y Yamada, M Sugiura, R Takayanagi, Y Sawada, T Iga
• Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 121 Issue 11 Pg. 793-8 (Nov 2001) ISSN: 0031-6903 [Print] Japan
• PMID: 11725547 (Publication Type: English Abstract, Journal Article)

Chemical References

• Benzimidazoles
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT3
• Serotonin Antagonists
• ramosetron

Topics

• Benzimidazoles (administration & dosage, metabolism, pharmacokinetics)
• Drug Administration Schedule
• Humans
• Injections, Intravenous
• Models, Biological
• Receptors, Serotonin (metabolism)
• Receptors, Serotonin, 5-HT3
• Serotonin Antagonists (administration & dosage, metabolism, pharmacokinetics)
• Time Factors