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.
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References
Arendt RM, Greenblatt DJ, Dejong RH, Bonin JD, Abernethy R, Ehrenberg BL, Giles HG, Sellers EM, Shader RI (1983) In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther 227:98–106
Bonetti EP, Pieri L, Cumin R, Schaffner R, Pieri M, Gamzu ER, Müller RKM, Haefely W (1982) Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects. Psychopharmacology 78:8–18
Brogden RN, Goa KL (1988) Flumazenil. A preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use. Drugs 35:448–467
File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 88:1–11
Friedman H, Abernethy DR, Greenblatt DJ, Shader RL (1986) The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma. Psychopharmacology 88:267–270
Gibaldi M, Perrier D (1982) Noncompartmental analysis based on statistical moment theory. In: eds Pharmacokinetics 2nd edn. Decker, New York, Basel, pp 409–424
Haefely W, Kyburz E, Gerecke M, Möhler H (1985) Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure activity relationships of their agonists and antagonists. Adv Drug Res 14:165–322
Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516
Lister RG, Greenblatt DJ, Abernethy DR, File SE (1984) Pharmacokinetic study on Ro 15-1788, a benzodiazepine receptor ligand, in the brain of the rat. Brain Res 290:183–186
Miller LG, Greenblatt DJ, Paul SM, Shader RI (1987) Benzodiazepine receptor occupancy in vivo: correlation with brain concentrations and pharmacodynamic actions. J Pharmacol Exp Ther 240:516–522
Möhler H, Richards JG (1981) Agonist and antagonist benzodiazepine receptor interaction in vitro. Nature 294:763–765
Polc P, Laurent J-P, Scherschlicht R, Haefely W (1981) Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn-Schmiedeberg's Arch Pharmacol 316:317–325
Timm U, Zell M (1983) Determination of the benzodiazepine antagonist Ro 15-1788 in plasma by high-performance liquid chromatography with UV detection. Arzneimittelforschung 33:358–362
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Mandema, J.W., Gubbens-Stibbe, J.M. & Danhof, M. Stability and pharmacokinetics of flumazenil in the rat. Psychopharmacology 103, 384–387 (1991). https://doi.org/10.1007/BF02244294
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DOI: https://doi.org/10.1007/BF02244294