Tag Archives: 3-hydroxyphenaze­pam

Kinetics of hydrolysis of 1,4-benzodiazepine derivative by carboxylesterases in mice organism

M. Ya. Golovenko, V. B. Larionov

A. V. Bogatsky Physics-Chemical Institute, National Academy of Sciences of Ukraine, Odesa;
e-mail: lvb_78@mail.ru

Chemical modification of the physiologically active substances and creation of prodrugs is one of the ways for pharmacotherapy optimization. The aim of the work was determination of the kinetic parameters of nonspecific esterases that catalyze hydrolysis of new hypnotic drug Levana (1,4-benzodiazepine derivative). The experiments were carried out using the 14C-labelled Levana and its active metabolite – 3-hydrixyphenazepam. In vitro it was shown that Levana undergoes spontaneous hydrolysis even in buffer solution (pH 7.4), though in plasma and homogenates of brain and liver this process is more intensive (conventional Vmax was 6.9 ± 0.5, 19 ± 4 and 12 ± 1 mM/(h∙mg of protein, correspondingly). The samples mentioned differ by activity of tissue estera­ses being most active in the liver (conventional Km 0.45 ± 0.04 mM for the liver and 47 ± 11 mM for the brain). In plasma carboxylesterase activity (for Leva­na) is the lowest (conventional Km 129 ± 10 mM). In vivo it was shown that Levana more easily permeates brain-blood barrier (compared to 3-hydroxyphenaze­pam), that leads to higher concentrations (after hyd­rolysis) of its metabolite in brain tissue. Also it is quantitatively estimated as the increase of concentration (brain/blood) ratio  ~1.4 times.