Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane andits N-desmethyl metabolite in the rat

The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have, been inves tigated in Wistar rats after 10 mg kg(-1) deramciclane fumarate was adminis tered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction techn ique was used to determine plasma levels of the parent compound and its N-d esmethyl metabolite. After oral administration the absorption of the parent compound was very fa st (t(max) 0.5 h). The maximum plasma concentration (C-max) was detected at 44.9, greater than or equal to 177.8 and greater than or equal to 2643.0 n g mL(-1) after oral, intraperitoneal and intravenous administration of dera mciclane, respectively. For the metabolite the respective C-max values were 32.0, greater than or equal to 25.4 and 51.0 ng mL(-1). The pharmacokineti c curves of both the parent compound and its metabolite showed enterohepati c recirculation for all administration routes. The biological half-life (t( beta 1/2)) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmet hyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC(0-infin ity) of deramciclane was 29.2- and 5.4-times higher than that observed afte r oral and intraperitoneal treatment, respectively. These AUC(0-infinity) r atios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% aft er intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the diff erent administration routes showed fast absorption. Furthermore, plasma lev els were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass meta bolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.