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Pharmacokinetic properties of imidazobenzimidazole derivative compound RU-1205 were investigated after subcutaneous administration to rabbits as a substance and a dosage form (lyophilisates for injection) at a dose of 25 mg/kg. The lyophilisate was characterized by high values of the relative bioavailability. In tests, the "hot plate" and "vinegar cramps" the dosage form and the substance exhibited the same analgesic effect.

We have studied the pharmacokinetics of drug-marker of cytochrome P450 isoenzyme CYP2C9 (losartan) and its metabolite E-3174 after subchronic oral administration of afobazole in doses 5 and 25 mg/kg in rats. The metabolic ratio (MR) of E-3174/Losartan was calculated. The pharmacokinetic parameters of losartan and its metabolite on the background of 4-day afabazole administration 5 mg/kg dose were not significantly different from analogous values calculated for the control group of rats. Therefore, afobazole in the effective anxiolytic dose did not change the MR value of metabolized P450 isoform. A five-fold dose increase in the afobazole dose led to significant difference in pharmacokinetic parameters, including A UC0-t, Cmax, Kel, t1/2el, MRT, CL/F, and Vd/F of losartan and AUC0-T, Cmax, and Tmax of E-3174. These findings are indicative of the induction of CYP2C9 isoenzyme by afobazole.

The effect of aphobazole on CYP1A2 (drug-marker caffeine) was studied in rats. Aphobazole was administered orally at doses 5 and 25 mg/kg, caffeine 50 mg/kg. The metabolic ratios (MR) for the caffeine metabolites (theobromine and paraxanthine) were accounted. After aphobazole administration at the effective, anxiolytic dose (5 mg/kg) for 4 days (3 times per day every 3 hours) neither the inhibiting nor the inducing effects on NOD1A2 was revealed. Increasing the aphobazole dose up to 25 mg/kg after 2 days repeated administrations of the drug made it possible to reveal a moderate inducing effect. Longer aphobazole administration (4 days), the inducing effect is amplified. Since the MR values on theobromine and paraxanthine after 2-day administration aphobazole exceed similar values in the control of 2.5 and 3.3 times, respectively. MR values after the 4-days aphobazole administration in dose 25 mg/kg exceed similar values in the control of 4.2 times for theobromine and in 6.1 times for paraxanthine.

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.

Metabolism of afobazole in rats has been studied using mass-spectrometry and HPLC, which revealed 17 products of afobazole biotransformation along with the parent compound. The structures of six afobazole metabolites were established and confirmed by comparison of HPLC retention times with the synthetic reference compounds and HPLC/mass spectrometry. Other metabolites were characterized by the masses of molecular ions. A significant fraction of the drug dose is biotransformed with the formation of hydroxylated benzimidazole moiety and oxidated morpholine.

Afobazole pharmacokinetics was studied after the administration via different ways in rats. After oral administration, afobazole is subject to intensive biotransformation with the formation of several metabolites (M-6, M-7, and M-11). The drug and its metabolites were detected in the blood plasma for 3 h and characterized by a high elimination rate after both oral and intravenous administration. Afobazole and its main metabolite (M-11) had a medium rate of permeability into brain (the target organ): the tissue availability was 0.584 for afobazole and 0.793 for M-11. The absolute bioavailability of afobazole upon oral administration was 43.6% for. Afobazole was completely absorbed from the gastrointestinal tract of rats and characterized by the first-pass effect, after which more than 40% of administered dose entered the circulation. The parent compound was determined in extremely low amounts in urine and feces: its content in 24-h urine on the average did not exceed 0.07% of the administered dose; in 24-h feces, it did not exceed 0.05 % after intravenous administration and 0.01% after oral administration).

The pharmacokinetics of befol at different routes of administration to animals and humans was studied. The therapeutic level of the drug concentration was established.