Pharmacokinetic disposition of the novel atypical anxiolytic CGS 9896 in the cynomolgus monkey.

The intravenous pharmacokinetic disposition of the novel, atypical anxiolytic CGS 9896 was studied in six cynomolgus monkeys. CGS 9896 was infused at dose levels of approximately 60, 120, and 240 micrograms/h/kg for a duration of 12 h, resulting in steady-state plasma concentrations averaging 38.4, 51.8, and 124 ng/ml, respectively. The average total systemic clearance was 35.3 ml/min/kg which was independent of dose and totally attributable to nonrenal pathways. The hepatic clearance was determined to be blood flow-rate dependent and the first-pass extraction calculated as approximately 84%. Both the apparent elimination rate constant and volume of distribution exhibited dose-dependent changes. Even though the plasma protein bound fraction was high (98.6%), no concentration dependency was observed. Furthermore, no concentration dependency was observed in the plasma/blood distribution ratio indicating the observed dose-related reduction in the volume of distribution may be attributable to nonlinear tissue uptake of CGS 9896.