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 plasma 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 hours. The brain/plasma AUC ratio for BMS-184111 concentration was 5.5, indicating effective penetration of the compound into the brain. Comparison of the plasma AUC values obtained following intravenous and intraperitoneal doses indicated that BMS-184111 was only 33% bioavailable after intraperitoneal administration, suggesting that the compound undergoes significant first-pass hepatic extraction. The oral bioavailability of BMS-184111 was found to be 10% after administration of the free 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 homogenate preparation (the 9000 g supernatant; S-9). Several of the metabolites thus generated were profiled using LC/MS and LC/MS/MS. Metabolism of BMS-184111 in rat liver S-9 occurs through hydroxylation, O-demethylation, and demethylenation.

Adriamycin(hydrazone)-antibody conjugates require internalization and intracellular acid hydrolysis for antitumor activity.

Adriamycin hydrazone (ADM-Hzn) immunoconjugates have previously been shown to exhibit antibody-directed antitumor activity in vitro and in vivo. In this report, the biological and biochemical properties of the mAb and linker were investigated. Conjugates prepared with two antibodies 5E9 [anti-(transferrin receptor)] and G28.1 (anti-CD37), (which internalize from the surface of target cells following binding) were more cytotoxic in vitro and had greater antitumor activity against Daudi B lymphoma tumor xenografts than a non-internalizing immunoconjugate prepared with mAb 2H7 (anti-CD20). In addition, the 13-acylhydrazone bond linking the drug to the mAb was labile at pH 5 and released unmodified ADM at a rapid rate (t1/2 = 2.5 h). Immunoconjugates prepared with an oxime linkage at the C-13 position were stable to acid and were not cytotoxic. These findings suggest that internalization of ADM-Hzn immunoconjugates and release of free ADM from the mAb in acidic intracellular compartments were important steps in the mechanism of action of ADM-Hzn immunoconjugates.