Pharmacokinetics and clinical use of flumazenil (Ro 15-1788)

Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist which can prevent or abolish selectively at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration flumazenil is rapidly absorbed (peak concentrations are achieved after 20 to 90 minutes), but bioavailability is low (16%) due to significant presystemic elimination. As less than 0.2% of an intravenous dose was recovered as unchanged drug in the urine, extensive metabolism must occur and so far 3 metabolites of flumazenil (N-demethylated and/or hydrolysed products) have been identified. For the clinical value of flumazenil a rapid onset of action is mandatory, which is facilitated by its fast uptake and regional brain distribution as verified by positron emission tomography. The limited duration of benzodiazepine-antagonistic action of flumazenil (2 to 3 hours) is due to its rapid hepatic elimination. This can be characterised either by the short half-life (0.7 to 1.3 hours) or better by the high plasma or blood clearance of 520 to 1300 ml/min (31 to 78 L/h). The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6 to 1.6 L/kg) or its partly flow-dependent hepatic elimination. Whereas in first trials flumazenil appeared to be without its own pharmacological effects, there is now increasing evidence that flumazenil is not devoid of intrinsic actions. Dependent on the dose, the basal clinical conditions and experimental tests, flumazenil has both weak agonist-like and inverse agonist-like properties which might be explained by a modulation of GABA-ergic activity. In several clinical studies intravenous doses down to 0.2mg of flumazenil initiated a rapid and reliable reversal of benzodiazepine-induced sedation, hypnosis or coma. Small incremental intravenous doses of 0.1 to 0.2mg of flumazenil are useful in benzodiazepine intoxications, in differential diagnosis of coma, excessive postoperative sedation and possibly in reversing paradoxical reactions of benzodiazepines. Because flumazenil is short acting, careful clinical observation is crucial. To maintain its antagonistic action repeated administrations will be necessary. At present, the therapeutic indications are restricted to some special situations. However, flumazenil is an interesting agent, which might contribute also to a better understanding and future development of more specific benzodiazepines, hopefully without the potential for dependence seen with existing compounds.