title: Biokinetics of gidazepam, derivatives of peptideaminobenzophenones and their metabolites.
abstract: 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.
authors.affiliation: Odessa Mechnikov State University, Ukraine. mzhuk@paco.net
authors.forename: O V
authors.initials: OV
authors.lastname: Zhuk
authors.forename: V G
authors.initials: VG
authors.lastname: Zinkovski
authors.forename: N Y
authors.initials: NY
authors.lastname: Golovenko
authors.forename: E A
authors.initials: EA
authors.lastname: Stankevich
authors.forename: M Y
authors.initials: MY
authors.lastname: Totrova
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000493:pharmacokinetics*; D001577:Benzophenones / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D004151:Dipeptides / Q000493:pharmacokinetics*; D051379:Mice; D008808:Mice, Inbred CBA; D011355:Prodrugs / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014149:Tranquilizing Agents / Q000493:pharmacokinetics
chemical_list: C121138:2-N-carbobenzylglycylglycylamido-5-bromobenzophenone; C121139:7-bromo-5-phenyl-dihydro-3H-1,4-benzodiazepine; D014151:Anti-Anxiety Agents; D001577:Benzophenones; D004151:Dipeptides; D011355:Prodrugs; D014149:Tranquilizing Agents; D001569:Benzodiazepines; C077010:gidazepam