塩酸アザセトロンの種々の投与計画における制吐作用のセロトニンの5-HT_3受容体結合占有に基づく解析

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Antineoplastic drugs have been shown to exert direct effects on the gut and induce the release of serotonin from the enterochromaffin cells of small intestinal mucosa. It is thought that released serotonin stimulates vagal afferent fibers through 5-HT_3 receptors located in the vagal afferent terminals in the gastrointestinal tract and initiates sensory signals to the area postrema and the emetic center, thereby initiating nausea and vomiting. A 5-HT_3 antagonist competitively inhibits serotonin at its specific binding sites, 5-HT_3 receptors, and thereby elicits an antiemetic effect. Therefore 5-HT_3 receptor occupancy of serotonin may be an appropriate indicator of the antiemetic activity of 5-HT_3 antagonists. We analyzed 5-HT_3 receptor occupancy of serotonin by integrating pharmacokinetic and receptor-binding kinetic parameters based on the receptor occupancy theory to compare the strength of the antiemetic effects of three dosage regimens of azasetron hydrochloride. The inhibitory effects on the binding of serotonin to 5-HT_3 receptor of regimen 2 (an intravenous bolus injection of 5mg of azasetron hydrochloride before and 8h after chemotherapy) and regimen 3 (an intravenous bolus injection of 2.5mg followed by 7.5mg continuous intravenous infusion for 24h) were longer-lasting than those of regimen 1 (an intravenous bolus injection of 10mg before the start of chemotherapy). Furthermore, a positive relationship was found between the time of inhibitory effects on the binding of serotonin to 5-HT_3 receptor and antiemetic effects of azasetron hydrochloride. From these results, dosage regimens 2 and 3 were considered to be more effective in the long term than regimen 1 in prophylaxis of nausea and vomiting induced by cisplatin.
社団法人日本薬学会の論文
2007-02-01

塩酸アザセトロンの種々の投与計画における制吐作用のセロトニンの5-HT_3受容体結合占有に基づく解析

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