Deramciclane Research Articles

Decrease of gluconeogenesis by deramciclane is counteracted by cytochrome P450 inhibitors

The effect of deramciclane (EGIS-3886), a new anxiolytic drug, was investigated on carbohydrate metabolism in mouse isolated hepatocytes. Deramciclane is a substrate of hepatic cytochrome P450 enzymes. Its in-vivo administration has been shown to cause a dose-dependent liver glycogen depleting effect in dogs. Hepatocytes were prepared from male CFLP mice (fed or starved for 24 h) using the collagenase perfusion method. The cells were incubated in Krebs-Henseleit bicarbonate buffer at 37°C with constant bubbling of CO2/O2 (5:95, v/v). Glucose production of the cells was measured in deproteinized samples by a glucokinase-glucose 6-phosphate dehydrogenase method. Glycogen content of the cells was determined with the same method after hydrolysis. Glycogen breakdown in mouse isolated hepatocytes was not affected by deramciclane. Gluconeogenesis from alanine or pyruvate but not from fructose was inhibited by high concentrations (40 μM) of deramciclane. The inhibitory effect of deramciclane on glucose production (nmol min−1/106 cells) from alanine was inhibited by econazole (-0.97 ± 0.13 vs -2.21 ± 0.49, P < 0.05, s.e.m., n = 5) or by SKF 525A (-0.60 ± 0.21 vs -2.21 ± 0.49, P < 0.02). Addition of deramciclane did not affect the level of cAMP or glutathione in isolated hepatocytes. The study shows that oxidative biotransformation of deramciclane decreases glucose formation from three carbon unit precursors without any direct effect on glycogen metabolism. We concluded that glycogen depletion by long-term deramciclane administration may be mediated by decreased gluconeogenesis caused by increased NADPH consumption upon oxidative metabolism of deramciclane.

Comparative pharmacokinetics of deramciclane in rat, dog, rabbit and man after the administration of a single oral dose of 3 mg kg-1

A comparative pharmacokinetic study of deramciclane fumarate (EGIS-3886), a new 5-HT2 antagonist with anxiolytic activity, was performed in rats, dogs, rabbits and healthy volunteers after the administration of a single oral dose of 3 mg kg−1. Considerable inter-species differences were revealed, particularly with respect to Cmax, AUC0-· and tβ1/2 values. Deramciclane showed rapid absorption in all cases (tmax: 0·3-2·6 h), whereas its elimination differed in different species (tβ1/2: 4·05–12·00 h in animals and 31·61 h in man). After the administration of a single 3 mg kg−1 oral dose of deramciclane, the AUC0-· value of the parent compound showed a significant species difference. The AUC0-· in rats, rabbits and dogs were 0·3, 13 and 21%, respectively, of that in man. The percentile ratio of unchanged deramciclane and total radioactivity (RDERAM) appeared to be extremely low and varied between 0·2 and 4·6%. The Vd kg−1 values suggested strong tissue binding in all the species studied. The plasma levels and pharmacokinetic parameters of N-desmethyl-deramciclane metabolite (EGIS-7056) were also studied and determined in the above species. The comparative pharmacokinetic study of deramciclane indicated an intensive biotransformation in all species although the rate of biotransformation appeared to be species-dependent.

Selective binding interactions of deramciclane to the genetic variants of human α 1-acid glycoprotein

Background α 1-Acid glycoprotein (AGP) plays a decisive role in the serum protein binding of several drugs.Genetic variants of AGP have different ligand binding properties. The binding of deramciclane (DER), a chiral anxiolytic agent, has been studied on A and F1/S genetic variants of AGP. Methods The effects of DER and reference drugs on the binding of specific fluorescent and circular dichroism (CD) probes of AGP were determined. Dicumarol (DIC) binding was measured by CD and equilibrium dialysis. Results DER effectively displaced probes bound to variant A, while it was less effective at displacing probes bound to variant F1/S. DER increased the binding and inverted the induced CD spectrum of DIC in the solution of variant F1/S. This phenomenon could not be brought about by the enantiomer of DER. Conclusion DER has high-affinity binding ( K a ≥ 2×10 6 M -1) to variant A, while its binding to the variant F1/S is about thirty times weaker. During simultaneous binding of DER and DIC to variant F1/S a ternary complex having about four times higher affinity is formed, in which the opposite chiral conformation of DIC is favored. General significance The binding interactions found prove that AGP can simultaneously accommodate different ligand molecules. Even weakly bound ligands can provoke unexpected allosteric protein binding interactions.

Covalent Protein Binding of a Minor Deramciclane Metabolite in Dog Plasma

The plasma protein interaction of a slowly eliminated substance which could be detected even after three weeks (about 0.2% of dose) in the plasma of Beagle dogs after a single oral administration of 10 mg kg−1 radiolabeled deramciclane, was determined. The substance, which could not be removed by extraction or displacement, was a metabolite irreversibly bound to serum albumin. The covalent adduct formed during the first 24 h after treatment, reached a maximum concentration between 1 and 4 days, and had an elimination half-life of approximately 10 days. The metabolite was isolated and subjected to mass spectrometry, and identified as a deramciclane derivative having a carboxylate group on the camphor ring.

Synthesis of Deramciclane labelled with radiocarbon in various positions

Synthesis of Deramciclane labelled with radiocarbon in various positions

A Sensitive, Validated Gas‐chromatographic Bioanalytical Method by Nitrogen Selective Detection of Deramciclane in Dog Plasma

A validated bioanalytical method has been developed for the determination of a new anxiolytic compound of deramciclane in dog plasma, using Lichrolut RP-18 solid-phase extraction and gas chromatography with nitrogen-phosphorous selective detector (GC-NPD). Gas-chromatographic separation was carried out by SPB-5 fused silica capillary column (30 m × 0·25 mm × 0·25 μm) after split injection, when the split liner was packed (3% silicone SE 30). An optimized two-level oven temperature program was used for the separation. The assay was validated with respect to selectivity, specificity, linearity, sensitivity, accuracy, precision, system suitability and plasma stability. All validation parameters were found to be within the internationally required limits. The limit of quantification of deramciclane in dog plasma was found to be 0·5 ng mL−1. The calibration curve showed good linearity (r=0·999) over the 0·5 and 100 ng mL−1 deramciclane plasma concentration range. The assay is sufficiently sensitive and relatively fast (12·5 min chromatographic run) to be used for routine monitoring and pharmacokinetic studies of deramciclane.