Multimodal liquid chromatographic separation methods in the study of ethimizol metabolism in man.

The metabolism of ethimizol in the human body has been investigated. Focus was on the detection and demonstration of the regioselective pathway of metabolic demethylation of ethimizol by determining the presence of the corresponding metabolites in blood, saliva and urine. Isolation, purification and identification of the metabolites present in the biological samples was achieved by applying a combination of the following methods: solid phase extraction, high performance liquid chromatography, high performance thin layer chromatography, nuclear magnetic resonance and mass spectrometry. The suggested chemical structures were definitely established by comparing the physicochemical characteristics of the ethimizol metabolites obtained from the individual biological fluids with the characteristics of synthetized authentic derivatives.

Dose-dependent pharmacokinetics of a xanthine-related nootropic drug, ethimizol, in rats.

Pharmacokinetics of the respiratory analeptic ethimizol, 4,5-bis(methylcarbamoyl)-1-ethylimidazole, with recently recognized nootropic properties, its metabolite 4-carbamoyl-5-methylcarbamoyl-1-ethylimidazole and of two metabolites of unknown structure was studied in plasma of rats after intravenous administration of the [2-14C]-labelled compound in 5 doses: 1.1, 3.3, 10, 20, and 30 mg/kg. The apparently monoexponential time course of dose normalized ethimizol plasma concentrations were not superimposable and the derived pharmacokinetic parameters were dose-dependent. The elimination rate constant and the initial volume of distribution decreased with increasing dose. The AUC versus dose relationship displayed disproportionate increases with increasing dose. Plasma ethimizol failed to obey the Michaelis-Menten kinetics and in an attempt to rationalize the observed nonlinearity a complete competitive product inhibition was suggested. Similar to the parent drug, the three metabolites exhibited a distinctly dose-dependent behavior as could be deduced from their dose-normalized concentration-time curves.

[Etimizol absorption from the small intestine in dogs: the dependence on dosage]. / Absorbtsiia étimizola iz tonkoi kishki sobak: zavisimost' ot dozy.

As etimizol has been previously reported to be of low bioavailability, the kinetics of its absorption from the dog intestinal loop was investigated in chronic experiments. After administration of etimizol at doses of 10 or 1 mg/loop mean residence time of etimizol in the loop was 20.1 and 7.6 min, respectively, with mean standard deviation being 3.1 and 0.8, respectively. It was concluded that overall etimizol absorption from small intestine was high and its low bioavailability resulted from presystemic drug metabolism, as well as that the absorption kinetics was dose-dependent, with saturation reached at higher drug doses.

Disposition of ethimizol, a nootropic drug, in rats and mice.

The pharmacokinetics of ethimizol, a nootropic drug, were studied in rats and mice using [2-14C]-4,5-di(methylcarbamoyl)-1-ethyl-imidazole. Autoradiography in mice injected iv showed a rapid and homogeneous distribution of the label into the tissues, brain included, and its excretion by the urinary pathway. The determination of ethimizol in plasma, organs, and excreta was based on combined extraction and the TLC procedure. In rats, the elimination half-life of ethimizol after iv administration of 10 mg/kg was 25 min, and its distribution volume was 1.4 liters/kg. The tissue/plasma concentration ratio for organs investigated was 1 immediately after iv administration, with a subsequent gradual increase. Based on this, saturable tissue binding of ethimizol in the liver, kidney, and brain was suggested. The drug was almost completely absorbed after administration, yet its systemic availability was only 32%. The brain uptake index of ethimizol was 101% as compared to 3H2O. Ethimizol was eliminated by metabolism. The labeled metabolites were predominantly excreted in the urine.

Pharmacokinetics of ethimizol in man.

The pharmacokinetics of ethimizol were studied in healthy volunteers given 1 mg/kg i.v. or 2 mg/kg orally. The serum concentrations of ethimizol were determined by HPLC. After i.v. infusion the kinetics of ethimizol could be described by a one-compartment model in 4 and by a two-compartment model in 1 subject. The elimination half-lives ranged from 34.1 to 79.2 min and the apparent volumes of distribution from 0.4 to 1.3 l/kg. After oral administration, the absorption half-lives ranged from 7.3 to 57.1 min. The absolute bioavailability varied between 3.6 and 22.2%. The binding of ethimizol to plasma proteins was less than 10%.

[Comparison of superslow activity with changes in the function of the neocortical cytostructures]. / Sopostavlenie sverkhmedlennoi aktivnosti s izmeneniiami funktsional'nogo sostoianiia tsitostruktur neokorteksa.

Effects of ethimizole on the infraslow ascillations of the brain electrical activity were correlated with the pattern of its distribution within cellular structures. A negative wave of the infraslow activity was found to occur after the drug administration at the moment of its maximal inclusion into the two cellular fractions: the nuclei and the surface proteins of the endoplasmatic net. These structures seem to play part in changes of the central nervous system's functional state.

Demethylation in vivo of a xanthine-related respiratory analeptic, ethimizol.

Demethylation of ethimizol in humans yielded 1-ethyl-4-carbamoyl-5-methyl-carbamoylimidazole. The formation, and the excretion in urine or saliva, of the other mono-N-demethylated ethimizol isomer, 1-ethyl-5-carbamoyl-4-methylcarbamoylimidazole has not been detected.

[Dynamics of the distribution of labeled etimizol in brain cell structures]. / Dinamika raspredeleniia mechenogo étimizola v tsitostrukturakh golovnogo mozga.

The time course of 14C-etimizol distribution in cell structures of the rat cerebral cortex was studied. Two minutes after intraperitoneal injection etimizol penetrates brain cells. At this time the greater portion of the drug is found in cytosol. In five minutes the maximal part of the label gets bound with cell nuclei and microsomal protein fraction extracted with 0.14 M NaCl. These two cell fractions show the highest radioactivity throughout the entire observation period (up to 7 days). Since these fractions are reported to be capable of calcium accumulation, a suggestion is made that metabolic effects of etimizol are likely to be related to calcium metabolism.

Determination of ethimizol and two of its metabolites in serum by high-pressure liquid chromatography.

A liquid chromatographic assay has been developed for the determination of ethimizol and two of its metabolites in serum. The analysed compounds are preseparated from serum by a micro-column packed with an octadecylsilanized silica gel. Components of the micro-column eluate are analysed on a silica-gel-packed column by means of a high-performance liquid chromatograph fitted with a photometric detector. At 262 nm the detection limit of the injected amount of ethimizol is about 5 ng. The mass spectra of two ethimizol metabolites isolated from rat serum are presented. The suitability of the developed assay for pharmacokinetic studies of ethimizol is demonstrated.