Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its 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 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.

[Pharmacokinetics and metabolism of tofizopam (Grandaxin)]. / A tofizopam (Grandaxin) farmakokinetikája és metabolizmusa.

Present publication summarizes the pharmacokinetics and metabolism investigations of anxiolytic tofizopam (Grandaxin) carried out in Hungary and in other countries. The pharmacokinetics and metabolism of tofizopam were studied in animals (mice, rat, rabbit, dog, monkey) and humans. The pharmacokinetics profile of the compound can be described by a two-compartment open model, where the absorption and distribution phase were found to be rapid (tmax 0.5-1.0 hour in rats and 1.0-1.5 hours in humans). The unchanged tofizopam and 14C-total radioactivity were eliminated from human plasma with a biological half-life (t beta 1/2) of 2.7-3.5 hours and 15-21 hours, respectively, which show a slower elimination of the metabolites. The main route of elimination was the excretion of the mainly conjugated metabolites after the intensive first-pass metabolism in urine and/or faeces, depends on the species. The major route of biotransformation was mono-, di-, tri- and tetra-o-demethylation in the various degree and positions of aromatic ring(s).