Elimination kinetics of the novel prodrug cinazepam possessing psychotropic activity in mice.

The kinetics of excretion of the novel tranquilizer cinazepam (3-hydroxy-7-bromo-5-(ortho-chlorophenyl)-1,2-dihydro-3H-1,4-benzdiazepin-2-one hemisuccinate (I)) in mice after a single administration and different schemes of multiple administration were determined. Mass balance was studied daily in excretions of mice (feces and urine) for 5-10 days. We observed that monoexponential renal excretion of (14)C-cinazepam and its metabolites predominated with all dosage regimens. Cinazepam and its metabolites were almost fully (> 90%) eliminated in urine and feces over the period of study (5-10 days), which means that no significant accumulation of the drug in the body occurred. The kinetic parameters of drug excretion were not significantly different after a single injection compared with those following multiple doses of (14)C-cinazepam administration. This finding suggests the absence of induction (repression) of enzymatic systems after multiple administration and lack of influence on the kinetic scheme of cinazepam elimination from mice. In our work, we also presented a modification of the Mansgeldorf's method for analysis of kinetic parameters during multiple administration of the tranquilizer. We demonstrated that our modified approach could be equally and efficiently applied for interpreting experimental data during a single dose administration and after chronic administration of xenobiotics. The use of this method made it possible to evaluate the relative efficiency of elimination processes and to find current values for excretion constants during sampling intervals.

Pharmacokinetics of a synthetic interferon inducer amixin in mice.

Pharmacokinetics of amixin, a synthetic interferon inducer, has been studied in mice under intravenous and oral routes of administration. Following oral administration, 80% of the drug was eliminated in the unchanged form. Its absolute biological availability comprised 0.7. In comparison to oral administration, after intravenous injection concentrations of amixin and its radioactive metabolites were higher during the first 5-120 min of the experiment in all organs and tissues. During the first 4-24 h, we observed an increase in the total radioactive material that was similar for both modes of administration. Low drug elimination rate was noted under both conditions. A novel integral model-independent method for estimation of equilibrium tissue-to-plasma partition ratios (K(p) has been proposed. The suggested integral parameter K(p) does not depend on the structure of the kinetic scheme and, most importantly, could be used for analysis of incomplete kinetic curves. We also propose a combined model that could help determine parameters of irreversible xenobiotic binding, the extent of the absorption from the intestine and relative efficacy of the hepatic excretion, in particular presystemic drug elimination.