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-carbobenzylglycy1-glyc ylamido-5 -bromobenzophenone (II) and their main physiologically active met abolite - 7-brom-5-phenyl-dihydro-3H-1,4-benzodiaze pine (III) were investi gated in mice. It was shown earlier that I undergoes intensive N(1_)desalky lation with the formation of a metabolite: (III) and products of its furthe r oxidation. Metabolism of II is characterized by hydrolysis of the peptide fragment and subsequent intramolecular condensation resulting in the forma tion of III, its oxi- and metoxylated derivatives and other minor metabolit es. The difference between kinetics of C-14-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 th e organs and tissues studied are not "stores" of slow exchange of C-14_ mat erial between serum and brain and are essentially different. After administ ration of I and I[I, the relationship between C-14-contents in brain and se rum change demonstrating a loop over the whole period of the experiment whi ch allows to suggest that serum acts as the central compartment, whereas br ain is a peripheral comparament of a kinetic scheme of distribution of prod rugs in mice.Following administration of III, we observed a linear relation ship between serum and brain C-14-contents which did not depend on the expe rimental 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 explai ned by the non-linearity of the processes of their biotransformation and sp ecific of biokinetics.