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

Abstract

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...

Essential oils found in the smoke of "tira-capeta", a cigarette used by some quilombolas living in pantanal wetlands of Brazil

“…Aoshima & Hamamoto (1999) verified that pinene potentiate the response in the presence of GABA at low concentrations, possibly because they bound to the potentiation-site in GABA(A) receptors and increase the affinity of GABA to the receptors. Also, Deramciclane, a camphor derivative, is an anxiolytic agent with a unique mechanism of action (Naukkarinen et al, 2005;Monostory et al, 2005). 1,8-Cineol showed anticonvulsant and hypnotic activities (Ismail, 2006).…”

Role of Cyp2e1 in Deramciclane Metabolism

“…It should be mentioned that cDNA-expressed CYP2E1 was active in N-demethylation of deramciclane, but the formation of N-desmethyl deramciclane (M4) did not increase as a result of isoniazid treatment. N-Desmethyl deramciclane (M4), which is considered a primary derivative of the parent compound, can be hydroxylated at various positions (Monostory et al, 2005). We think that CYP2E1 induction may result in some elevation of N-demethylase activity, but hydroxylation as a second step causes consumption of N-desmethyl deramciclane at the same time.…”

“…The amounts of deramciclane metabolites were calculated on the basis of digital autoradiography by a Berthold digital autoradiograph type LB-287 (EG&G; Berthold Technologies, Bad Wildbad, Germany). The metabolites were identified on the basis of their R f values on thin layer compared with authentic standards or on the basis of mass spectrometric analysis as previously described (Monostory et al, 2005). The rates of metabolite formation in the presence or absence of inhibitors were determined.…”

“…Its anticonvulsant activity is exerted via inhibition of synaptosomal ␥-aminobutyric acid uptake (Kovács et al, 1989). Our previous work (Monostory et al, 2005) identified the structures of the metabolites formed during the biotransformation of deramciclane in rat, mouse, rabbit, dog, and human primary hepatocytes. Deramciclane underwent side chain modification and oxidation at several positions of the molecule.…”

Biological Networks: Comparison, Conservation, and Evolution via Relative Description Length

“…One explanation is that the metabolic network of human is indeed more similar to the metabolic network of mouse than to the metabolic network of rat. Mouse and rat are both popular lab animals, and many papers deal with the similarity of certain metabolic pathways in human and in mouse or rat (Monostory et al, 2005;John et al, 2000;Raffaï et al, 2001;Edsbacker et al, 1987;Mori et al, 1985). Some metabolic pathways seem to be more similar in human and rat (Mori et al, 1985), while others seem more similar in human and mouse (Edsbacker et al, 1987).…”