Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin.

5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5-HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5-HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin.