Method for Individualized Evaluation of Antiemetic Effect Induced by 5-HT₃ Receptor Antagonist

Abstract

5-HT 3 receptor antagonists are widely used for prevention of chemotherapy-induced nausea and vomiting, though their antiemetic effects vary among patients. We investigated a method for evaluation of antiemetic effects in individual patients. We used the 5-HT 3 receptor occupancy of serotonin for our evaluation, which was estimated based on the plasma concentration of granisetron and concentration of serotonin near the 5-HT 3 receptor in the small intestine, obtained by measuring the urinary concentrations of granisetron and 5-hydroxyindoleacetic acid (5-HIAA)/creatinine (Cre). The mean cumulative percent for urinary excretion of granisetron at 24 h after administration and coefficient of variation were 16.19±6.30% and 38.91%, respectively. The time course of urinary concentration of 5-HIAA/Cre also varied among the patients. The value for 5-HT 3 receptor occupancy of serotonin without granisetron was higher than that prior to administration (blank), thus most treated patients had the possibility of induced emesis. In contrast, that with granisetron was lower than the blank value, indicating that those treated patients would not develop emesis. Furthermore, the estimated 5-HT 3 receptor occupancy of serotonin in the small intestine and actual individual patient condition corresponded well, showing the validity of our method. Our results suggest that it is possible to evaluate individual antiemetic effects by estimating the 5-HT 3 receptor occupancy of serotonin in the small intestine based on plasma concentrations of granisetron and serotonin near the 5-HT 3 receptor in the small intestine using noninvasive urine samples. This method of individual evaluation is considered to be useful and effective.Key words urinary 5-hydroxyindoleacetic acid; 5-HT 3 receptor occupancy; granisetron; 5-HT 3 receptor antagonist; antiemetic effect Chemotherapy-induced nausea and vomiting can lead to discontinuation of treatment and decrease the quality of life of affected patients. One of the main mechanisms of these adverse effects induced by antineoplastic agents is activation by serotonin of 5-HT 3 receptors, which exist on vagus nerve afferent fibers in the small intestine mucous membrane. With antineoplastic drug administration, serotonin is released from enterochromaffin cells, which synthesize and secrete this neurotransmitter, and stimulates 5-HT 3 receptors on adjacent vagal afferent nerves. Depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex.1) Therefore, the concentration of serotonin near 5-HT 3 receptors in the small intestine may be an indicator of the degree of emetic action. Serotonin is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which is subsequently excreted in urine. Moreover, a relationship between the frequency of vomiting and cumulative urinary excretion of 5-HIAA after administration of cisplatin (50 mg/m 2 ) has been reported.2) As a result, the urinary concentration of 5-HIAA may also be a helpful indicator of the degr...