Stability and pharmacokinetics of flumazenil in the rat

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Abstract
The pharmacokinetics of flumazenil in the rat were determined after 2.5 mg/kg intravenous and 25 mg/kg oral administration. Following intravenous administration flumazenil was rapidly eliminated with an extremely short terminal half-life (mean±SE,n=8) of 8.3±0.3 min due to a large total blood clearance of 147±7 ml/kg/min combined with a relatively small volume of distribution at steady-state of 1.33±0.07 l/kg. After oral administration flumazenil was rapidly absorbed; however, the bioavailability was low (28±4%) and variable. Flumazenil was found to be unstable in rat blood in vitro and disappeared with a half-life (mean±SE,n=5) of 8.3±1 min and 31±4 min at body and room temperature, respectively. The blood samples were stabilized by addition of sodium fluoride (NaF) and cooling to 0°C. The samples had to be stored at −35°C when analyzed at later times. Presumably esterases in rat blood are responsible for the observed instability. A sensitive HPLC assay to measure flumazenil concentrations in small blood samples is also described.