Pharmacokinetics of ethanol in mice with different alcohol motivation.

We studied the pharmacokinetics of (14)C-ethanol administered in various doses and via different routes to CBA, C57Bl/6, and (CBAxC57Bl/6)F1 mice. Kinetic scheme of ethanol distribution included its elimination by enzymatic (80-90% C(0)) and exponential (10-20% C(0)) mechanisms. Ethanol pharmacokinetics did not depend on the administration route and mouse strain. The kinetic scheme of ethanol distribution in mice was characterized by a dose-dependent linear increase in alcohol concentration in the plasma and brain and nonlinear (parabolic) increase in the area under its pharmacokinetic curve in the test tissue.

Biokinetics of transdermal therapeutic medicinal form of phenazepam.

We studied the rate of phenazepam absorption into the blood and its transport to the brain from a transdermal therapeutic system and bioavailability of the drug in this system. Hydrogel matrix consisting of polyvinyl alcohol and 1,2-propylene glycol was used for application. Transdermal application of 0.1-0.4 mg phenazepam in a dose of 14 mg/kg provided a stable level of this drug during application interval (1-48 h), while its bioavailability for blood plasma and brain was 0.63 and 0.2, respectively (determined for 0.4 mg phenazepam). The rate of drug penetration into the blood and brain was 46 and 60 ng/ml/h, respectively.

[Biokinetics of a new prodrug gidazepam and its metabolite]. / Biokinetika novogo prolekarstvennogo preparata--gidazepama i ego metabolita.

Pharmacodynamics and pharmacokinetics of a novel tranquilizing agent--gidazepam (I), a prodrug, and its physiologically active metabolite--7-bromo-5-phenyl-1,2-di-hydro-3H-1,4- benzodiazepine-2-one (II) in mice organism were studied. The form of relationship was determined between the dynamics of the anticonvulsant effect of labelled (2-14C-) I and II and the kinetics of the content of 14C-compounds in the experimental animals brain. It was noted that the biophase of the effect and the effector fragment of the scheme of biokinetics for I and II are identical. The effector prognosis of pharmacokinetics of I was realized. The comparison of the main characteristics of biokinetics for the prodrug (I) and drug (II) allowed us to reveal the nature of the quantitative differences of these pharmacological effects.

[Effector modeling of the action of ligands of the GABA receptor complex: functional interactions of muscimol and exogenous modulators of the complex]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa: funktsional'noe vzaimodeistvie mustsimola i ékzogennykh moduliatorov kompleksa.

In comparison with the literature data the pharmacological effects of muscimol (MS) on mice organism were studied under the condition of administration of the exogenic ligands of GABA-receptor complex GABA antagonist bicuculline (BC), chloride ionophor blocking agent pentylenetetrazole (PZ), phenazepam (BD), sodium barbital (BB) and GABA synthesis antagonist--thiosemicarbazide (TS). Antagonism of MS to the anticonvulsant effect of BB and BD at the administration of BC to the animal was observed, while no effect was observed at the administration of PZ. However at the administration of TS to the experimental animals MS exhibits anticonvulsant effect. The observed properties (partial agonism/partial reverse agonism) of MS at its effect to the whole system are probably determined by the level of endogenic GABA and its changes due to the administration of TS and functional state of GABA--receptor system modified with the exogenic ligand BC.

[Effector modeling of the action of ligands of GABA-receptor complex. Functional interaction of the hypothetic alcohol receptor with other subunits of the complex]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa. Funktsional'noe vzaimodeistvie gipoteticheskogo retseptora spirtov s drugimi sub"edinitsami kompleksa.

The types of the interaction of the pharmacological effects of ethanol and barbiturate antagonists--picrotoxin, bemegride and corasol--were determined. The effect of ethanol was determined as competitive--for the convulsant effects of bicuculline, and non-competitive--for the effects of thiosemicarbazide. The indices of the anticonvulsant effects of n-aliphatic alcohols were compared. It is suggested that n-aliphatic alcohols alter the functional status of the supramolecular GABA-receptor channel ensemble. The pharmacological properties and the elements of the structural similarity of picrotoxin and n-propanol (the presumptive ligand of the GABA-receptor channel ensemble) are discussed.

[Effector modelling of the action of ligands of the GABA-receptor complex, cooperativity of the processes and the type of modification of the complex by convulsants and their reversible agonists]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa, kooperativnost' protsessov i tip modifikatsii kompleksa sudorozhnymi agentami i ikh obratnymi agonistami.

The expression of cooperativity of pharmacological effects of convulsants--exogenic ligands of supramolecular GABA-receptor-channel ensemble (GABA-RC)--bicuculline, picrotoxin, pentylenetetrazole, bemegride at intravenous infusion to intact animals and against a background of administration of barbital-Na and phenazepam is determined. The supposed mechanism of bemegride effect is discussed. Analysis of principles of GABA-RC functioning in vivo on the base of pharmacological data (cooperativity coefficients and types of modulation of GABA-RC functions at the interaction of convulsants and their reverse agonists) suggests the formation of biosystem response at modification of structures adequate to one of four subunits of "quartet" (tetrameric) model of GABA-RC.

[Effector modeling of the effect of ligands of GABA receptor complex. Modification of conformation states of the complex by combined administration of benzodiazepines and barbiturates]. / Effektornoe modelirovanie deistviia ligandov GAMK-retseptornogo kompleksa. Modifikatsiia konformatsionnykh sostoianii kompleksa pri sovmestnom vvedenii benzodiazepinov i barbituratov.

The dynamics of the anticonvulsive effect (antagonism to the pharmacological effects of korazol, bicuculline, and picrotoxin) of sodium barbital, phenazepam, diazepam and their structural analogues was studied at their individual and combined administration. The indices of the combined pharmacological effect of barbiturates and benzodiazepines are not the summation of the pharmacologic effects of the compounds. The mutual influence of the effects of exogenic ligands--convulsive agents and anticonvulsive compounds was studied which can be considered as a result of the hyperbolic modification of three states of the GABA-receptor complex.

[Correspondence of mouse organs and tissues to the central and peripheral compartments of the kinetic model based on the drug-metabolite ratio in blood plasma and other tissues]. / Sootvetstvie organov i tkanei myshei tsentral'nomu i perifericheskomotsekam kineticheskoi modeli, osnovannoe na dannykh sootnosheniia lekarstvo/metabolit v plazme krovi i drugikh tkaniakh.

The kinetic scheme of distribution of a structural analogue of phenazepam 7-brom-5-phenyl-1,2-dihydro-3H-1,4-benzdiazepine-2-on (I) and its main metabolites in the mouse body was presented. The process parameters were compared with the parameters of mouse body distribution of other N1-unsubstituted derivatives of 1,4-benzdiazepine. It was shown that for the original preparation fatty tissue, liver, spleen, myocardium may be referred to the central compartment of the kinetic scheme of distribution. No organ or tissue functioning as the peripheral compartment of the kinetic scheme of the drug distribution was found. The gastrointestinal tract of the experimental animals can serve as the peripheral compartment of the kinetic scheme for products of biotransformation of I.

[Transport and metabolism of a membrane-active complexon in the mouse body]. / Transport i metabolizm membranoaktivnogo kompleksona v organizme myshei.

Two-phase decrease in content of N-(3H-aminoacetyl)-I-aza-4,7,10,11-tetraoxacyclopentadecane hydrochloride (ATCH) and of its metabolites as well as absence of accumulation were observed in mice tissues. Kinetic parameters of 3H-products elimination estimated by means of sequental logarithmation enabled to suggest that ATCH and its free metabolites were intensively involved in biotransformation of molecules. 3H-glycine was found not to be a product of the ATCH metabolism. High and stable level (from 10 min up to 24 hrs) of water soluble and protein-bound derivatives of ATCH were found in mice liver tissue and blood plasma after intravenous administration of the macroheterocycle.

[Kinetics of the excretion of a membrane-active macroheterocycle from the body in mice]. / Kinetika vyvedeniia membranoaktivnogo makrogeterotsikla iz organizma myshei.

The study of the excretion kinetics of N-(3H-aminoacetyl)-I-aza-4,7,10,13-tetraoxacyclopentadecane hydrochloride and its metabolites with the mouse urine and feces showed a high relative effectiveness of the urinary excretion (only some 2% of the dose is excreted with the feces). It was also found that there occurs an intensive biotransformation of the compound yielding free and water-soluble metabolites.

[Mass-spectrometric analysis of 2-aminobenzophenone derivatives and their metabolites]. / Mass-spektrometricheskii analiz proizvodnykh 2-aminobenzofenona i ikh metabolitov.

Mass-spectrometry analysis was carried out for 2-aminobenzophenone, its halogen derivatives and metabolites formed in the rat organism. The characteristic fragmentation patterns were outlined for the products arising on hydroxylation of the above compounds. The structural specificity in the oxidation of 2-aminobenzophenones was found to be different from that predominant in hydroxylation of phenyl (o-chlorophenyl) ring of 1,4-benzodiazepines which give on hydrolysis the respective benzophenones.

[Comparative analysis of the pharmacokinetics of N1-unsubstituted derivatives of 1,4-benzodiazepine]. / Sravnitel'nyi analiz farmakokinetiki N1-nezameshchennykh proizvodnykh 1,4-benzodiazepama.

Parameters of 14C-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine-2 and its main metabolite distribution in the blood plasma and brain of mice were compared with phenazepam and nordiazepam distribution. Constant ratio of blood plasma 14C-7-bromo-5-phenyl-1,2-dihydro-3A-1,4-benzodiazepine-2, its 3-hydroxy metabolite and other derivatives' level to brain level was noted vs their changing content in the mentioned test objects. Characteristic peculiarities of the distribution of initial 1,4-benzodiazepines and their metabolites and its predictive value are discussed.

[Factors affecting the metabolism and distribution of phenazepam in subcellular fractions of animal hepatocytes]. / Faktory, izmeniaiushchie metabolizm i raspredelenie fenazepama v subkletochnykh fraktsiiakh gepatotsitov zhivotnykh.

Metabolism and intracellular distribution of 14C-phenazepam and its derivatives were studied in rat and mice liver tissue. Phenazepam was found mainly in microsomal fraction of the animal hepatocytes, where rapid turnover of the substance occurred. The metabolites formed were uniformly distributed in the cell and penetrated into other tissues. The rates of phenazepam metabolites conjugation and binding with proteins were dissimilar in rat and mice tissues. Metabolism of phenazepam was shown to depend on doses of the drug administered. Incorporation of phenazepam into liposomes affected distinctly its turnover in mice tissues.

[Dispersion analysis used for assessing the anticonvulsant activity of 1,4-benzodiazepines]. / Ispol'zovanie dispersionnogo analiza dlia otsenki protivosudorozhnoi aktivnosti 1,4-benzodiazepinov.

A study was made of the time course of alterations in the convulsant activity of corazol after injection to mice of 1,4-benzodiazepine derivatives with different chemical structure. Significant anticonvulsant effect of benzodiazepines was observed for 5--120 minutes and was regarded a dynamic index. The maximal action of the drugs was observed within 15--30 minutes. The most pronounced anticonvulsant action was recorded after administering phenazepam and its 3-hydroxyderivative. The dependence of the anticonvulsant effect on the time of experiment and structure of the test compounds was examined by single-factor analysis of variance. The results demonstrate the relationship of differences in the anticonvulsant effects to the time factor and differences in the structure of the test compounds.

[Genetic differences in the excretion of phenazepam-14C]. / Izuchenie geneticheskikh razlichii v vyvedenii fenezepama-14C.

Content of 14C-phenazepame and its metabolites was studied in feces and urine of mice strains C57BL/6 and BALB/ c after intraperitoneal administration of the preparation at a dose of 14 mg/kg. Concentration of phenazepame and of its trihydroderivative was higher in urine of the BALB/c strain mice than in C57BL/6 strain that corresponded to genetic differences of the tranquilizer metabolism in the animal strains studied.

[Genetic differences in the anticonvulsant effect and rate of metabolism of phenazepam]. / Izuchenie geneticheskikh razlichii v protivosudorozhnom éffekte i skorosti metabolizma fenazepama.

The metabolic rate of 14C-phenazepam (14 mg/kg) in male C57BL/6 and BALB/c mice and F1 hybrids (BALB/c X C57BL/6) and the anticonvulsant effect of the tranquilizer in hybrid mice were studied. It was demonstrated that oxidation of the phenazepam molecule in the third position in BALB/c mice and in F1 hybrids proceeded at a higher rate than in C57BL/6 mice. The sensitivity to the anticonvulsant effect of phenazepam in C57BL/6 animals was greater than in BALB/c mice and F1 hybrids.

[Nature of the relation between the anticonvulsant action of phenazepam and its concentration in mouse brain]. / Kharakter vzaimosviazi mezhdu protivosudorozhnym deistviem fenazepama i ego soderzhaniem v golovnom mozge myshei.

A method has been suggested for simultaneous recording of the content of 12C-phenazepam and its metabolites in the mouse brain and of minimum effective doses of corasole intravenously that induce the tonic extension of the animals. Parameters of the two-compartmental kinetic model of absorption, distribution and elimination of 14C-products in the mouse brain were determined. These processes conform to the first order kinetics. A correlation was disclosed between the content of radioactive products in the animals' brain and minimum effective doses of corasole. A linear decline of the anticonvulsant action of phenazepam was revealed during the experimental period. Radiochromatography enabled one to detect the parent compound and its 3-hydroxy metabolite in mouse brain extracts.