SERUM-PROTEIN BINDING OF LERISETRON, A NOVEL SPECIFIC 5HT(3) ANTAGONIST, IN PATIENTS WITH CANCER

The aim of this study was, (1) to characterize the serum protein bindi ng of lerisetron, a new 5-hydroxytryptamine (5-HT3) receptor antagonis t under investigation as an antiemetic agent and (2) to measure the pe rcentage of unbound lerisetron in cancer patients. The binding paramet ers were determined in human serum albumin (HSA), alpha(1)-acid glycop rotein (AAG) and in pooled serum from six healthy volunteers. Concentr ations of lerisetron ranging from 50 ng/ml to 2 mu g/ml were used. The serum protein binding of C-14-lerisetron (2 mu g/ml) was determined b y ultrafiltration in three groups of individuals. Group I comprised he althy subjects (n = 11), group II comprised cancer patients undergoing radiotherapy (n = 9), and group III comprised cancer patients receivi ng chemotherapy (n = 18). The unbound concentration of lerisetron was measured in all samples by liquid scintillation counting. Concentratio ns of both AAG and HSA were also measured in all serum samples. The dr ug was extensively bound in pooled serum. involving a nonsaturated pro cess. In HSA, lerisetron was also highly bound (4.04 +/- 0.8% unbound) and the protein binding was essentially unchanged within the studied concentration range of lerisetron. The extent of binding to AAG was hi gh but significantly lower than in serum and in HSA and was also indep endent of lerisetron concentration. The unbound lerisetron was signifi cantly decreased in group II cancer patients when compared with group I subjects (2.38 +/- 0.64% vs 3.70 +/- 0.70%; P < 0.001). No significa nt changes in lerisetron binding were observed in group III patients. HSA was diminished in both groups of patients and AAG was only signifi cantly increased in group II. Unbound lerisetron was correlated with A AG in group II and with HSA in group III.