5-HT_3受容体拮抗薬である塩酸ラモセトロンの活性代謝物を考慮した受容体結合占有理論に基づく解析

概要

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Severe nausea and vomiting induced by antineoplastics diminish the patient's quality of life and ability to tolerate further chemotherapy. Ramosetron hydrochloride is a-5HT_3 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 syudy, in order to analyze the pharmacological effect of ramosetron hydrochloride in a comprehensive manner, we estimated the 5-HT_3 receptor occupancy after intravenous administration of ramosetron hydrochloride using pharmacokinetic parameters and the dissociation constants for the 5-HT_3 receptor. The average total receptor occupancy after intravenous administration of 0.3 mg of ramosetron hydrochloride to human was calbulated to be 82.9%(ramosetron, 77.8%;M-1, 5.1%), thus exhibiting a significant antiemetic activity. Furthermore, the estimated time course of 5-HT_3 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-HT_3 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.
社団法人日本薬学会の論文
2001-11-01