IN-VIVO DISPOSITION AND IN-VITRO METABOLISM OF AN ANXIOLYTIC COMPOUND, BMS-184111, IN RATS

Plasma concentrations of BMS-184111, an anxiolytic, were determined as a function of time following single intravenous, intraperitoneal and oral administrations. In order to assess the brain penetration of this compound, concentrations in whole brain samples were also determined in the intravenous leg of the study. Concentrations of BMS-184111 in p lasma and brain homogenate samples were determined using an HPLC assay following liquid/liquid extraction. After intravenous administration, BMS-184111 was eliminated from plasma with a half-life of about 3.6 h ours. The brain/plasma AUC ratio for BMS-184111 concentration was 5.5, indicating effective penetration of the compound into the brain. Comp arison of the plasma AUC values obtained following intravenous and int raperitoneal doses indicated that BMS-184111 was only 33% bioavailable after intraperitoneal administration, suggesting that the compound un dergoes significant first-pass hepatic extraction. The oral bioavailab ility of BMS-184111 was found to be 10% after administration of the fr ee base and 23% after administration of the hydrochloride salt. These results suggest that BMS-184111 undergoes incomplete GI absorption and /or intestinal metabolism in addition to first-pass hepatic extraction . The in vitro metabolism of BMS-184111 was studied using rat liver ho mogenate preparation (the 9000 g supernatant; S-9). Several of the met abolites thus generated were profiled using LC/MS and LC/MS/MS. Metabo lism of BMS-184111 in rat liver S-9 occurs through hydroxylation, O-de methylation, and demethylenation.