Valivodz I. Pharmacokinetics of 3-alkoxyderivatives of 1,4-benzodiazepine

The thesis is dedicated to the study of the pharmacokinetics of 3-alkoxyderivatives of 1,4-benzodiazepine. For these derivatives, a high rate and extent of absorption from the gastrointestinal tract, a rapid distribution between the internal organs and tissues, and elimination in the form of a number of metabolites were found. The alkoxyderivatives metabolism processes include both classical pathways (hydroxylation and methylation) and the elimination of the alkoxy radical forming a 3-hydroxyderivative. The distribution of propoxazepam in the internal organs and tissues in the dose range of 10-45 mg/kg can be determined as a linear process of mass transfer with a rapid redistribution of the compound between the organs and the blood. The absorption degree reaches ~ 85%, the small intestine was defined as a nonspecific «absorption window». Induction of cytochrome P450 (CYP3A4) by phenobarbital leads to a statistically insignificant increase in the total radioactive products amount and the ratio of individual groups of metabolites in mouse excretions upon intragastric administration of a 14C-derivative. Prolonged propoxazepam administration does not change the parameters of its excretion. The low impact on the enzyme systems that carry out its biotransformation is confirmed by the absence of statistically significant changes in the elimination constant before and after the course administration.