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.

Intraperitoneal chemotherapy of ovarian cancer by hydrogel depot of paclitaxel nanocrystals

“…IP chemotherapy has proven more effective than intravenous (IV) therapy in several clinical studies [2, 10, 11]. Furthermore, part of the IP-administered drug is slowly absorbed to systemic circulation and provides sustained systemic effects [12–14]. In 2006, the National Cancer Institute issued an official announcement encouraging the clinical use of combined IP and intravenous (IV) chemotherapy for patients with optimally resected stage III ovarian cancer, based on clinical evidence of survival benefits [15].…”

Comparison of the Effects of Deramciclane, Ritanserin and Buspirone on Extracellular Dopamine and Its Metabolites in Striatum and Nucleus Accumbens of Freely Moving Rats

“…Notably, smaller doses of deramciclane fumarate (3 or 10 mg/kg) were practically inactive, and 10 mg/kg even decreased DOPAC levels in nucleus accumbens. In rats, 3 and 10 mg/kg of deramciclane fumarate produce plasma levels that are close to or higher than the anxiolytic plasma levels in human beings [48,49]. Even doses one-fifth or one-tenth of those have been effective in several anxiolytic animal models [27,28].…”

Biotransformation of Deramciclane in Primary Hepatocytes of Rat, Mouse, Rabbit, Dog, and Human

“…N-Desmethyl-deramciclane has been reported to have receptor-binding characteristics and pharmacological activity similar to those of the parent compound. Previous studies proved that N-desmethyl deramciclane was also formed in vivo in several animal species Nemes et al, 2000;Magyar et al, 2002) and in humans (Huupponen et al, 2004).…”