Pharmacokinetics of the new benzodiazepine antagonist Ro 15‐1788 in man following intravenous and oral administration.

Abstract

1 During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. 2 Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 1 kg-l. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.141 min1 resulted in a short elimination half-life of less than 1 h. 3 No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. 4 Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. 5 Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

Plasma pharmacokinetics and metabolism of the benzodiazepine antagonist [11C] Ro 15-1788 (flumazenil) in baboon and human during positron emission tomography studies

“…The total volume of distribution calculated here (Vd area : 44.0 ± 17.0 1) was of the same order as previously reported: 47.86 ± 12.37 I (19), 0.63 ± 0.18 llkg (18), 1.01 ± 0.17 and 1.11 ± 0.23 llkg (1). The plasma clearance value of 40.0 ± 8.5 lIh was also in good agreement with the value of 41.5 ± 1.3 lIh(18), and only slightly lower that the values 1226.8 ± 185.9 mlImin (i.e, 73.56 ± 11.15 lib) and 14.8 ± 2.3 mlIminlkg (i.e, 53.28 ± 8.28 lib for standard 60 kg subject) reported in two other studies(1,19) after administration of unlabelled tlumazenil.…”

“…Abbreviations: SRA = specific radioactivity, TLC = thin layer chromatography, HPLC = high performance liquid chromatography Flumazenil (Ro 15-1788) is an imidazo-benzodiazepine lacking the aromatic cycle in position 5 typical of the benzodiazepine structure (1). It is a highly specific, selective antagonist of the central benzodiazepine receptor (CBZR) (2,3) which has been in clinical use for several years in toxicology Ro 15-17111 Parent drug -f1umazenil…”

Pharmacokinetics and Clinical Use of Flumazenil (Ro 15-1788)

“…L) were observed after 20 to 90 minutes. Because of high hepatic clearance, and consequent first-pass metabolism, the oral bioavailability of flumazenil is low and averaged only 16% (Roncari et al 1986). However, because of the rapid onset of action re-5 quired, and the short elimination half-life, flumazenil is normally administered intravenously.…”

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

“…Flumazenil. Flumazenil is rapidly and fully absorbed from the gastrointestinal tract (peak concentrations are achieved after 20 -90 min), and extensive firstpass hepatic metabolism results in a low systemic bioavailability (16%) (Roncari et al, 1986). Flumazenil is extensively metabolized in the liver to N-demethylated and/or hydrolyzed metabolites, because less than 0.2% of the dose is recovered as unchanged drug in the urine (Klotz et al, 1984).…”