Stability and pharmacokinetics of flumazenil in the rat.
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 degrees C. The samples had to be stored at -35 degrees 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.
Mandema
J W
JW
Center for Bio-Pharmaceutical Sciences, University of Leiden, The Netherlands.
Gubbens-Stibbe
J M
JM
Danhof
M
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005442:Flumazenil / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
D005442:Flumazenil