A. A. Prokopov

Experimental evaluation of bioavailability of tetramezine from tablets

The absolute bioavailability f of the new antipsychotic drug tetramezine from tablets with intestine-soluble shell upon peroral administration in dogs amounted to 65.4% and was significantly higher than upon administration in the form of an aqueous solution of the parent substance (f = 48.1%). Comparative data on the peroral administration of the aqueous solution of tetramezine in dogs and rats showed that the bioavailability of tetramezine in dogs (48.1%) was much higher than that in rats (10%). The higher bioavailability of tetramezine from tablets is due to the intestine-soluble shell, which prevents the premature biotransformation of the drug in the acid medium of the stomach.

Tetramezine metabolism in rats

The metabolism of the novel antipsychotic drug tetramezine in rats was studied using a computer-aided gas chromatography-mass spectrometry system. After peroral and intramuscular administration in rat, the drug is eliminated from the organism in the form of two metabolites. One of these is unambiguously identified as 1-(β-aminoethyl)-3,3-dimethyldiaziridine; the structure of the other metabolite also has a diaziridine framework. A considerable proportion of tetramezine is eliminated in the unchanged form.

Experimental Pharmacokinetics of Tetramezine in Rats

The pharmacokinetics of the new psychotropic agent tetramezine in rats has been studied with the aid of gas chromatography. The drug concentration profiles in the blood, excreta, and urine have been determined. Upon peroral administration, tetramezine is rapidly absorbed from the gastrointenstinal tract, and the maximum drug concentration in the blood plasma is observed within 5 min. The pharmacokinetics of tetramezine upon intravascular and intramuscular injections are dose-dependent and linear within the dose range studied. The average half-elimination times are 0.42 h (i.v.); 0.32 h (i.m.); and 0.42 h (p.o.). The obtained data are important for the subsequent investigation of the drug bioaccessibility and metabolism and for establishing relationships between the drug behavior in vitro, in experiments on animals, and in clinics.

Adsorption capacity of hydroxyapatite for several amino acids and heavy metal ions

The adsorption capacity of hydroxyapatite for several amino acids and heavy metal ions was investigated. The quantitative characteristics and laws of adsorption were determined. Possible adsorption mechanisms were discussed.

Investigation of tetramezine excretion from rats

The excretion of the novel antipsychotic agent tetramezine in rats was investigated using gas chromatography. Upon a single intramuscular administration in a dose of 200 mg/kg, only 5.2% of the introduced drug was recovered in the unchanged form, which implies that feces and urine are not the major routes of tetramezine excretion. The results suggest that tetramezine is well absorbed and the major proportion of it is subject to biotransformation, so that metabolism is the principal mechanism of clearance. The renal clearance (0.15 liter/(h · kg)) and half-elimination time (0. 37 h) for tetramezine in rats are determined using the experimental pharmacokinetic parameters (elimination constant and distribution volume).

Studying phenozan acid metabolism in rabbits

The metabolism of a new antioxidant agent — phenozan acid — was studied in rabbits. The main directions of this process are (i) oxidation of benzene ring with the formation of 2,6-di-tert-butyl-p-benzoquinone and (ii) dehydration of the propionic acid fragment with the formation of 4-hydroxy-3,5-di-tert-butylphenylacrylic acid methyl ester. The structures of metabolites were established by computer-aided gas chromatography/ mass spectrometry and confirmed by direct synthesis.

Experimental pharmacokinetics of fenozan acid and fenoxan in rabbits

The experimental pharmacokinetics of the new antioxidant preparations — fenozan acid and fenoxan (potassium salt of fenozan acid) — were studied in rabbits by monitoring the concentration profiles of the drugs in the blood plasma. Upon peroral administration in a single dose of 100 mg/kg, both fenozan acid and fenoxan are rapidly absorbed into the blood, their maximum concentrations peaking within 12 min after administration. The dynamics of the fenozan acid concentration in the blood plasma upon peroral administration was described by a one-compartment pharmacokinetic model, and that upon the intravenous injection, by a two-compartment model. The pharmacokinetic parameters characterizing the distribution and elimination of fenozan acid and fenoxan were close for both peroral administration and intravenous injections. Fenozan acid was slowly eliminated from the rabbit organism, the mean retention times being 11.3 and 11.8 h; the half-elimination times, 8.28 h and 7.68 h; and the stationary distribution volume, 20.8 and 37.5 liter/kg (i.v. versus p.o., respectively), which is indicative of intracell penetration of the drug and its trapping by organs and tissues. The relatively low value (F = 57.8%) of the bioavailability of fenozan acid upon peroral administration is related to a presystemic metabolism of this drug.

Investigation of Tetramezine Binding to Plasma Proteins in Healthy Donors

It was established that about 30% of the administered dose of tetramezine was bound to plasma proteins in healthy donors. This should not significantly influence the strength of its pharmacological action in the absence of binding to blood cellular components.

Iodometric Assay of Tetramezine Content in Tablets

Amethod for the iodometric assay of tetramezine in tablets was developed. The relative error of the assay was no greater than 3.5%.

Hydrolytic Stability of Albicar

Albicar underwent noticeable hydrolytic cleavage only under forcing conditions (high temperature, strong acid). Albicar in solutions for injection was shown to be highly stable under sterilizing conditions.