ABSTRACT:The metabolic fate of deramciclane [(1R,2S,4R)-(؊)-2-phenyl-2-(2-dimethylamino-ethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane], a new anxiolytic drug candidate, has been determined in rat, mouse, rabbit, dog, and human hepatocytes. Rat and rabbit cells were the most active, whereas the rate of metabolism was quite slow in human hepatocytes. During biotransformation, deramciclane underwent side chain modification and oxidation at several positions of the molecule. The side chain modification led to the formation of N-desmethyl deramciclane and phenylborneol. The oxidation of deramciclane resulted in several hydroxy-, carboxy-, and N-oxide derivatives. The hydroxylation took place at primary or secondary carbons of the camphor ring as well as at the side chain; furthermore, dihydroxylated derivatives were also found. The side chain-modified metabolites were also oxidized to hydroxy-or carboxy-derivatives. Conjugation of phase I metabolites, as a route of elimination, was also observed in rat, rabbit, and dog hepatocytes. Although there were some species differences in biotransformation of deramciclane, it was concluded that phase I metabolism in human liver cells seemed to be similar to the metabolism in the hepatocytes isolated from rat. With careful approach, the rat model may be considered to be predictive for human metabolism of deramciclane.The early knowledge of routes by which a new drug candidate may be metabolized is important for the interpretation of pharmacological and toxicological data obtained in drug development studies. Furthermore, information on species differences in the rates and pathways of metabolism is of great interest and will help to select the laboratory animal species most suitable to study the toxic properties of drugs (Gillette, 1995;Vermeulen, 1996). Primary hepatocytes in metabolic studies can offer a simple and useful model, since they retain most of the metabolic capabilities of the intact liver and provide an opportunity to study the biotransformation of novel drugs at a very early stage in the drug development process (Maurel, 1996). The potential advantages of such an approach include the relatively high amounts of metabolites formed during the incubation, the easy extraction procedure of the metabolites from the medium and the cells, and the high purity for further analysis.In the last few years, efforts have been made to develop new non-benzodiazepine-type anxiolytics with minimal risk of sedative and muscle relaxant side effects in the therapeutic dose range. Deramciclane, developed by EGIS Pharmaceuticals Ltd. (Budapest, Hungary), is a novel potential anxiolytic agent that is more effective than diazepam or chlordiazepoxide (Gacsályi et al., 1988;Berényi et al., 1990). Deramciclane has been shown to be a potent and relatively specific 5-HT2A/2C receptor antagonist in receptor binding and functional studies (Palvimaki et al., 1998). Its anticonvulsant activity is exerted via inhibition of synaptosomal ␥-aminobutyric acid uptake (Kovács et al., 1989). Our work demons...

The distribution of 3H-labelled deramciclane (EGIS-3886), a new 5-HT2 antagonist with anxiolytic activity, has been investigated by whole-body autoradiography and quantitative organ-level determination after intravenous and oral administration to male and female rats at a dose of 3 mg kg(-1). Pregnant dams were also studied, but by autoradiography only. In the autoradiographic study 32 organs were investigated, while in the quantitative organ-level study the radioactivity in 15 organs were determined. There are no sex differences in the distribution of deramciclane, absorption is rapid, elimination is comparatively fast, no specific organ is targeted, and the accumulation of the compound is very unlikely. Penetration of the blood-brain barrier was complete and extremely fast, a very important feature of a potential anxiolytic drug. There is no penetration of the foetus in pregnant dams. The study demonstrated that deramciclane has advantageous pharmacokinetic properties in rats.

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The time related distribution and pharmacokinetics of double-labelled EGIS-3886 (EGIS-3886-phenyl-14C and -ethyl-3H) were studied in the plasma, hypophysis and 14 cerebral regions, including the spinal cord of the rat after a single oral treatment (acute experiments) and after repeated administration of one dose daily for six days (subacute experiments). The tissue levels of EGIS-3886 (deramciclane) were calculated from the simultaneously determined dpm values and the specific activities of the two radioisomers present in the dose administered. EGIS-3886 was rapidly absorbed from the gastrointestinal tract (t(max)=1.0 h). The concentration-time curves in the tissues can be described by a two compartment open model. The 3H-activity could be measured during the whole period of the acute experiment (96 h), whereas 14C-radioactivity fell below the detection limit within 24 h. The AUC(0-96) values for 3H were 10 to 15 times higher than that for 14C. In all samples examined, on the concentration time curves a peak characteristic of enterohepatic cycle can be seen at 12 h. The studies indicated that intact molecules entered brain tissues from the circulation. The results of the subacute experiments indicate that the 14C-labelled EGIS-3886, or its metabolite(s) carrying the tracer, reach an equilibrium as early as on the second to third day, whilst the level of 3H-radioactivity continually increases during the six days of repeated administration. In the subacute experiments the peak concentrations were reached at 0.5 h after the final treatment. However, their values for 3H were higher than in acute experiments. The last tendency was not observed in the case of 14C-tracer. The AUC values of 3H-labelled EGIS-3886 determined in subacute experiments predominated over 14C; the ratios were 50 to 60 in all brain regions. The enterohepatic cycle, seen after a single dose, also operated after repeated dosage. The time related concentrations of EGIS-3886 in the hypophysis were at least two times higher than that in the plasma and the brain tissues. No significant difference was seen in the concentrations of EGIS-3886 in the symmetrical (left and right) regions of the brain.