Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds

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Abstract

The pharmacokinetics of deramciclane and especially the fate of its side chain were studied in rats after oral treatment, using 3H- and 14C-labelled (ring- or side chain labelled) deramciclane and 14C-dimethylamino-ethanol (14C-DMAE) radioisomers. The labelled compounds were admixed and the total radioactivities of both labels were simultaneously determined. The data obtained from the analysis of the plasma concentration–time curves revealed that an intensive cleavage (30–40%) of the side chain occurred at the ether bond. The core of deramciclane, carrying the ring label, was almost completely eliminated during 24 h, while the elimination of the side chain was very slow (tβ1/2: 99 h). The side chain residue most probably represents dimethylamino-ethanol, but the presence of dimethylglycine (DMG) cannot be excluded. The AUC0–∞ and the MRT values of DMAE were found to be much higher than those of the parent compound. In addition to the plasma levels, the time related changes of the tissue concentrations of the radioisomers of deramciclane were analysed both in the brain and the hypophysis. The concentration–time curves have shown similar characteristics to those of the plasma, but higher concentrations were reached in both organs (the highest in the hypophysis). It is postulated that the low rate of formation and elimination of the metabolite(s) (DMAE or DMG) indicates that, due to their endogenous nature, they can be incorporated into choline/acetylcholine or protein synthesis.

Introduction

Deramciclane is a novel non-benzodiazepine type of anxiolytic compound, which in a therapeutic dose range lacks the potentiating effect of ethanol, i.e. muscle relaxant activity and sedative properties (Gacsályi et al., 1988, Gacsályi et al., 1996). A relatively strong plasma protein (albumin, acidic glycoprotein) binding of deramciclane was found in different species (Visy et al., 1996).

Receptor binding studies revealed its high affinity to 5-HT2A and 5-HT2C receptor subfamilies (Gacsályi et al., 1996, Gacsályi et al., 1997, Pälvimäki et al., 1998). Several pharmacokinetic studies were carried out earlier on animals (rat, dog, rabbit) and on humans, and significant species variations were found in the pharmacokinetic properties of deramciclane (Kanerva et al., 1998a, Kanerva et al., 1998b, Kanerva et al., 1999a, Kanerva et al., 1999b, Klebovich et al., 1998, Hazai et al., 1999, Balogh Nemes et al., 2000).

Our previous pharmacokinetic studies with deramciclane-ethyl-14C revealed that the 14C-label of the side chain can be detected both in plasma and in the tissues of rats several days after drug administration (Magyar et al., 1998). By contrast, using deramciclane-phenyl-14C or deramciclane-camphor-3H radioisomers, labelling the core of the molecule, almost the total amount of radioactivity left the body within 24 h (Lengyel et al., 1998a). The dissociation observed in the radioactivities (labelling the side chain and the core of the molecule by 14C and 3H, respectively), indicates an intensive cleavage of the compound at the ether bond. The intensity of the process depends on species, being ∼30–40% in rats and dogs. According to our present studies, the rate of the side chain cleavage is less intensive in humans (unpublished observation). The persisting tissue levels of radioactivity derived from the side chain prompted us to study its fate in the body.

In our present investigations rats were treated orally with a mixture of alternatively labelled radioisomers of deramciclane and 14C-DMAE, which provided a new sensitive method to study the fate of the side chain in rats.

Section snippets

Chemicals

Deramciclane fumarate (EGIS-3886; CAS 120-444-78-8; (1R,2S,4R)-(−)-N,N-dimethyl-2-{(1,7,7-trimethyl-2-phenylbicyclo-[2,2,1]-hept-2-yl)oxi}ethaneamine-2-(E)-butendioate (1:1)) was synthesised by EGIS Pharmaceuticals (Budapest, Hungary). All other chemicals used in these studies were purchased from Reanal (Budapest, Hungary) and Merck (Darmstadt, Germany); their quality was of analytical or chromatographic grade.

Radioactive substances

Deramciclane-phenyl-14C (specific activity: 1.37 GBq/mmol), deramciclane-camphor-3H

Results

The time related changes in plasma concentrations of rats treated with the mixture of the radioisomers of deramciclane-camphor-3H and deramciclane-ethyl-14C, or deramciclane-camphor-3H and DMAE-14C, or deramciclane-phenyl-14C and calculated on the basis of total radioactivity are presented in Fig. 2. A striking difference was found between the plasma levels of DMAE and the radioisomers labelled at the core of deramciclane. The plasma level of DMAE-14C could be measured during the whole

Discussion

Our earlier and present pharmacokinetic studies with deramciclane-phenyl-14C, camphor-3H and -ethyl-14C radioisomers indicated that in rats the side chain was cleaved at the ether bond and at least a small fraction of the side chain residue eliminated at a lower rate compared to the core of the molecule (Lengyel et al., 1998b, Magyar et al., 1998; Fig. 1). The cleavage of the ether bridge by the microsomal enzymes results in the formation of aldehyde, which can preferentially be further

Acknowledgements

The authors wish to thank to Maria Knippel for her technical help in preparing the manuscript. Special thanks are due to Ágota Walter and Tibor Nagy for their careful work during the study.

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