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

• Published in: Journal of pharmacy and pharmacology Vol. 52; no. 1; p. 47
• Main Authors: Nemes, K B, Abermann, M, Bojti, E, Grézal, G, Al-Behaisi, S, Klebovich, I
• Format: Journal Article
• Language: English
• Published: England 01.01.2000
• Subjects: Administration, Oral; Animals; Anti-Anxiety Agents - administration & dosage; Anti-Anxiety Agents - blood; Anti-Anxiety Agents - pharmacokinetics; Area Under Curve; Biological Availability; Bornanes - administration & dosage; Bornanes - blood; Bornanes - pharmacokinetics; Half-Life; Injections, Intraperitoneal; Injections, Intravenous; Male; Molecular Structure; Rats; Rats, Wistar
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1211/0022357001773670

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.