Pharmacokinetics of deramciclane, a novel anxiolytic agent, after intravenous and oral administration.

Abstract

Deramciclane is a new compound that has shown anxiolytic effects in animal experiments and in human studies. The aim of this study was to determine the pharmacokinetic parameters of deramciclane after intravenous and oral administration, and its oral bioavailability. Deramciclane 30 mg was given intravenously and orally as a tablet and as solution in an open, randomised, crossover three-period trial to 12 healthy male volunteers. Oral bioavailability of deramciclane and the pharmacokinetic parameters of deramciclane and N-desmethylderamciclane, the principal metabolite, were determined after intravenous and oral administration of the parent drug. The first and second distribution half-lives (mean +/- SD) of deramciclane were 0.04 +/- 0.01 and 3.03 +/- 0.50h, respectively, and the half-life of the elimination phase was 26.6 +/- 5.5h. The clearance of deramciclane after an intravenous dose was 0.24 +/- 0.10 L/kg. The elimination phase half-life of N-desmethylderamciclane was 38.2 +/- 6.9h after intravenous and about 25 h after oral dosing of the parent compound. The mean oral bioavailability of deramciclane was 44% (range 27-58%) and 36% (23-50%) after administration of the oral solution and tablet, respectively. Deramciclane was well tolerated even after a 30 mg intravenous dose resulting in peak plasma concentrations 10 times higher than observed after its oral administration. After intravenous administration, the pharmacokinetics of deramciclane are adequately described by a three-compartment model. After oral administration its pharmacokinetics follow a two-compartment model with first-order absorption. The elimination phase half-life of the parent compound is similar after intravenous and oral administration, whereas the apparent half-life of N-desmethylderamciclane is longer after intravenous than after oral administration of the parent compound. The oral bioavailability of deramciclane is large and uniform enough to allow its clinical use as tablets.