title: Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat.
abstract: The pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mgkg(-1) deramciclane fumarate was administered orally, intraperitoneally or intravenously. A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite. After oral administration the absorption of the parent compound was very fast (t(max) 0.5h). The maximum plasma concentration (C(max)) was detected at 44.9, > or =177.8 and > or =2643.0 ngmL(-1) after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, > or =25.4 and 51.0 ngmL(-1). The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tbeta 1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90-5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-infinity, of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-infinity ratios 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% after intraperitoneal administration. The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.
authors.affiliation: Department of Pharmacokinetics, EGIS Pharmaceuticals Ltd, Budapest, Hungary.
authors.forename: K B
authors.initials: KB
authors.lastname: Nemes
authors.forename: M
authors.initials: M
authors.lastname: Abermann
authors.forename: E
authors.initials: E
authors.lastname: Bojti
authors.forename: G
authors.initials: G
authors.lastname: Grézal
authors.forename: S
authors.initials: S
authors.lastname: Al-Behaisi
authors.forename: I
authors.initials: I
authors.lastname: Klebovich
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001892:Camphanes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar
chemical_list: D014151:Anti-Anxiety Agents; D001892:Camphanes; C406721:N-desmethylderamciclane; C060555:deramciclane