Drug interactions and clinical pharmacokinetics of flumazenil

Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist that can selectively prevent or abolish at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration, flumazenil is absorbed rapidly (peak concentrations are achieved after 20-90 min absorption half-life 0.3 h) but bio-availability is low (16%) owing to significant pre-systemic elimination. As less than 0.2% of an i.v. dose is recovered as unchanged drug in the urine, extensive metabolism must occur and so far three metabolites of flumazenil (N-demethylated and/or hydrolysed products and corresponding glucuronides) have been identified. In the clinical use of flumazenil, rapid onset of action is mandatory. This is facilitated by its fast uptake and regional brain distribution, as verified by positron emission tomography (PET). The limited duration of the benzodiazepine-antagonistic action of flumazenil (2-3 h) is due to its rapid hepatic elimination. This can be characterized either by the short half-life of 0.7-1.3 h or, better, by the high plasma and blood clearance of 520-1300 ml min-1. The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6-1 kg) or its partly flow-dependent hepatic elimination. In interaction studies with healthy volunteers, with either midazolam, lormetazepam and flunitrazepam or ethanol, it was found that the disposition of flumazenil was not affected by co-administration of these four drugs. Consequently, pharmacokinetic interactions between benzodiazepines (or alcohol) can be ruled out. So far the pharmacokinetics of the antagonist have been evaluated only in healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)