Lerisetron is an antagonist of serotonin type 3 (5-HT3) receptor, with antiemetic activity.

5-HT3 receptor (cell-free assay):0.81 μM

showed a decrease in total clearance and distribution volume of the central compartment in old rats. The lerisetron free (unbound) fraction remained unchanged among the groups, and there were no significant differences in alpha(1)-acid glycoprotein levels. The concentration-effect relationship was best described by a sigmoid E(max) model. Since the drug concentration in plasma at half-maximal effect (EC(50)) decreased in old rats, an increased sensitivity to the effect of lerisetron in old animals could be expected.

Fischer 344 rats (n = 44) were divided into three groups, depending on their age: 5, 13, and 25 months. Blood samples were collected before administration of 200 micro g/kg of lerisetron for measurements of albumin, alpha(1)-acid glycoprotein, and unbound fraction of lerisetron. The lerisetron plasma concentrations were measured by high-performance liquid chromatography. A two-compartment model was fitted to the data using the nonlinear mixed-effects computer program WinNonMix. The population analysis was performed with the complete set of the collected data, and the potential sources of variability in the population parameters were investigated. Additionally, a pharmacodynamic study was performed. The effect of lerisetron (inhibition of the von Bezold-Jarisch reflex) was evaluated in young, adult, and senescent Fischer 344 rats.