Biokinetics of gidazepam, derivatives of peptideaminobenzophenones and their metabolites.

Results of a comparative study of biokinetics of two prodrugs gidazepam (I) and the derivative of peptideaminobenzophenone, 2-N-carbobenzylglycyl-glycylamido-5-bromobenzophenone (II) and their main physiologically active metabolite-7-brom-5-phenyl-dihydro-3H-1,4-benzodiazepine (III) were investigated in mice. It was shown earlier that I undergoes intensive N1-desalkylation with the formation of a metabolite: (III) and products of its further oxidation. Metabolism of II is characterized by hydrolysis of the peptide fragment and subsequent intramolecular condensation resulting in the formation of III, its oxi- and metoxylated derivatives and other minor metabolites. The difference between kinetics of 14C-contents in organs and tissues of mice following administration of prodrugs I, II and their metabolite III are demonstrated: In the first two cases no rapid distribution phase of I and II was detected; maximal levels of III were achieved faster (0.25-0.35 min) and its elimination proceeded with higher rates. For all substances the organs and tissues studied are not "stores" of slow exchange of 14C-material between serum and brain and are essentially different. After administration of I and II, the relationship between 14C-contents in brain and serum change demonstrating a loop over the whole period of the experiment which allows to suggest that serum acts as the central compartment, whereas brain is a peripheral compartment of a kinetic scheme of distribution of prodrugs in mice. Following administration of III, we observed a linear relationship between serum and brain 14C-contents which did not depend on the experimental time. This finding suggests that the studied biosubstrates act as one (central) compartment of a kinetic scheme of distribution of III. It is demonstrated that the peculiarities of their pharmacologic action of prodrugs are explained by the nonlinearity of the processes of their biotransformation and specific of biokinetics.

[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.

[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.

[Prediction of the parameters of the accumulation of 1,4-benzodiazepine derivatives in the body of mice based on their excretory kinetics]. / Prognozirovanie parametrov nakopleniia v organizme myshei proizvodnykh 1,4-benzdiazepina na osnove ikh kinetiki vyvedeniia.

Kinetics of 14C-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-one (I) excretion from the mouse body following a single and long-term administration of the compound was studied. It was shown that kinetics of excretion of total radioactive material in the urine and feces is a sum of monoexponential processes. Prediction of the compound accumulation in the mouse body during its long-term administration was performed. Parameters of accumulation of the compound, diazepam, chlordiazepoxide and phenazepam were compared. Significant, reciprocally compensated changes in relative efficacy and the rate of excretion of total radioactivity in the urine and feces during a long-term administration were noted. It is recommended to take into consideration the events studied at a chronic administration of derivatives of 1,4-benzodiazepine.

[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.