Absolute bioavailability of himantane in rabbits.

Pharmacokinetic parameters of himantane and its metabolites in the blood plasma of rabbits were compared after single administration of himantane solution in a dose of 25 mg intravenously and 100 mg orally. It was established that the original substance is characterized by low absolute bioavailability (7.95%). Himantane is subjected to first-pass effect and is extensively metabolized in the liver to metabolites with m/z 266 and 250.

Excretion of himantane and its metabolites with the urine and feces in rats.

The levels of himantane and its metabolites in daily urine and feces of rats were measured after intraperitoneal and oral dose of 25 mg/kg. The injected dose of the initial substance and 1.3% its metabolites were eliminated with excrements within 24 h after administration via both routes 0.23%.

Excretion of compound M-11 and its metabolites with urine and feces in rats.

The excretion of compound M-11 and its metabolites with the urine and feces was studied in rats after intraperitoneal and oral administration in a dose of 25 mg/kg. Experiments showed that 1% metabolites were detected in excretions over 24 h irrespective of the route of administration, while the initial compound was not found even in trace amounts.

Permeability of the blood-brain barrier for dilept and its active metabolite.

Experiments on rats with measurements by HPLC-MS/MS showed that antipsychotic preparation dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) administered per os in doses of 40 and 200 mg/kg crossed the blood-brain barrier and was detected in rat brain (unchanged drug and its active metabolite N-caproyl-L-prolyl-L-tyrosine). The brain/plasma distribution coefficient for dilept was 2.0, for metabolite 0.5. No dose-concentration relationship was found, presumably because of the high dose of the drug transported from the blood to the brain not only by free diffusion, but also with participation of active carriers, whose number was limited.

[Pharmacokinetics of hemantane in rats].

The pharmacokinetics ofhemantane after administration in different ways has been studied in rats. It is established that hemantane introduced both orally (p.o.) and intravenously (i.v.) is very intensively metabolized, with the main metabolites characterized by m/z = 250 and 266 and detected for 6 hours after the administration in both ways. Hemantane shows high rate of permeability into its target organ--brain--whereas the permeation of its metabolites is extremely low. The absolute bioavailability ofhemantane upon p.o. administration was 14.1%. The substance is subject to the "first-pass effect". The unchanged substance was determined in daily urine and feces in very small fractions of the administered dose: 0.23% in urine and 0.08% in feces after i.v. administration and 0.02% in feces after p.o. administration. Thus, it may be concluded that the substance is completely absorbed in rats from the gastro-intestinal tract into systemic blood circulation.

[Pharmacokinetics of afobazole metabolite (M-11) in rats].

Pharmacokinetics of compound M-11 (main metabolite of afobazole) after administration via different routes was studied in rats. After oral and intravenous administration, M-11 exhibited weakly pronounced bioconversion with the formation of a few metabolites that could be detected in plasma samples for about 3 hours. The absolute bioavailability of M-11 after oral administration was 68.3%. It was found that M-11 was completely absorbed from gastrointestinal tract of rats and characterized by "the first pass effect", after which approximately 70% of administered dose entered the circulation. The parent substance was determined neither in urine nor in feces.

Comparative analysis of tissue availability for afobazole and compound M-11.

Comparative analysis of pharmacokinetic parameters of afobazole and its main metabolite M-11 after single intraperitoneal injections of their solutions (25 mg/kg) to rats showed much more intense penetration of M-11 compared to afobazole into rat tissues and organs, judging from the area under the pharmacokinetic curve (AUC) and maximum concentrations (C(max)). The half-life periods (T(l/2e)l) of afobazole and M-11 were similar.

[Model study of afobazole distribution in pregnant and lactating female rats and infant rat pups].

Afobazole and M-11, its major metabolite were detected in placental and embryonic rat tissues after single peroral administration to pregnant female rats at a dose of 100 mg/kg. The anxiolytic drug and its metabolite are also detected in rat milk and body of the breast-fed infant rat pups after 4 days of daily administration (200 mg/kg, per os) to lactating female rats.