Metabolism of a New Dipeptide Neuroprotector in Rats.

Metabolism of a new neuroprotector GZK-111 (N-phenylacetylglycyl-L-proline ethyl ester) in rat blood plasma was studied by HPLC-mass spectrometry. Four biotransformation products were identified. It is concluded that the main ways of GZK-111 biotransformation are hydrolysis of the ester bond by esterases followed by degradation of the resulting metabolite, as well as reactions leading to the formation of phenylacetic acid and cycloprolylglycine that exhibits neuropsychotropic activity.

Preclinical Pharmacokinetics of GZK-111, a Dipeptide with Neuroprotective Activity.

We studied the pharmacokinetics of GZK-111 (N-phenylacetyl-glycyl-L-proline ethyl ether), a compound with neuroprotective activity, and its metabolite CPG (cyclo-L-prolylglycine) in rat blood plasma after single intravenous and intragastric administration in a dose of 20 mg/kg. It was found that the parent drug undergoes intensive biotransformation; its metabolite CPG persists in the circulation more than twice as long as GZK-111 and its plasma concentrations were higher by 50-70 times than the concentrations of the parent compound.

Comparative Preclinical Pharmacokinetics and Bioavailability of Antidepressant GSB-106 Tablet Form.

Pharmacokinetics and relative bioavailability of antidepressant GSB-106 (hexamethylendiamide bis-(N-monosuccinyl-L-seryl-L-lysine) were determined in rabbits after single oral administration of the pharmaceutical substance and tablet mass. GSB-106 concentrations in the blood plasma were determined by HPLC-mass spectrometry. Relative bioavailability of GSB-106 tablet form was 160.79±24.33%.

Metabolism of a Novel Anxiolytic GML-1 in Rats.

Metabolism of a novel anxiolytic GML-1 (N-benzyl-N-methyl-1-phenylpyrrolo[1,2-a]pirazin-3-carboxamide) in rat blood plasma was studied by HPLC-mass spectrometry. Three biotransformation products with the corresponding molecular ions were detected. A conclusion was made that the main pathways of GML-1 metabolism are oxidative reactions yielding hydroxylated, methylated, and demethylated metabolites.

[Pharmacokinetic evaluation of afobazole pharmaceutical composition with modified release].

The main pharmacokinetic parameters (AUC0-∞, Tmax, Cmax, Cl/F, t1/2 el, MRT, Cmax/AUC0-I, Vd/F) of afobazole base in a new pharmaceutical composition and afobazole dihydrochloride substance after single peroral administration have been determined in rats. The availability of afobazole base pharmaceutical composition relative to that of the substance amounted to 153.2%.

[EVALUATION OF THE PHARMACOKINETIC INTERACTION OF AFOBAZOLE WITH CYP2C9 ENZYME DRUG SUBSTRATE OF CYTOCHROME P450].

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.

[Specific features in pharmacokinetics of the original neuroleptic dilept in animals and humans].

Interspecies differences in pharmacokinetics of the original neuroleptic drug dilept have been studied in experimental animals (rabbits and rats) and volunteers after single oral administration of tablets and tablet mass of the drug. Parent drug in the rabbit blood plasma was detected for 4 h, in the rat plasma for about 2 h, and in the human blood plasma for about 1 h after drug administration. The degrees of dilept biotransformation into metabolites (defined as metabolism intensity, AUCM/AUCP) in rats were 21.3 (for M-1) and 1645 (for M-2), in human volunteers - 5.8 and 658.5, and in rabbits - 1.6 and 125.8, respectively. Thus, the intensity of drug metabolism in experimental animals and volunteers was different and decreased in the series rats humans rabbits.

Comparison of pharmacokinetics and relative bioavailability of tablets and substance of new dipeptide neuroleptic dilept.

We studied pharmacokinetics of dilept after single cross-administration of tablets and substance of dilept in a dose of 40 mg to rabbits. The following pharmacokinetic parameters were calculated: maximum plasma concentration of dilept, time to maximum observed concentration, area under the pharmacokinetic curve, elimination half-life, and relative bioavailability. Dilept concentration in blood plasma was estimated using ultra-fast liquid chromatography with mass spectrometry detection. Relative bioavailability of dilept tablets was 93.46±28.91% of that for the substance.

[Clinic pharmacokinetics of a new original antipsychotic drug Dilept].

The pharmacokinetic study of a new original antipsychotic drug Dilept in healthy volunteers was performed. Volunteers received Dilept as single 20, 40 or 60 mg tablets. The parent drug in the human blood plasma was detected in low concentrations and short-term time due to intensive biotransformation with formation of two metabolites N-caproyl-L-prolyl-tyrosin (M-1) and N-caproyl-L-prolin (M-2). After 20 and 40 mg of Dilept parent drug was detected in certain time points and after 60 mg for 1 h. M-1 and M-2 metabolites were registered in the blood plasma for 4 - 8 h. Theirs concentrations were 10 - 100 times higher of unchanged drug ones. Metabolites pharmacokinetics in the studied dosage range was nonlinear.

[In vivo study of the pharmacokinetic interaction of afobazole and losartan (cytochrome CYP2C9 substrate)].

The influence of afobazole on isoenzyme CYP2C9 production in rats was studied using losartan as the marker drug. Single dose of losartan was administered orally without afobazole in a dose of 30 mg/kg and in the same single (30 mg/kg) on the background of 3- and 4-day administration of afobazole in a dose of 5, 25, 75, 100, and 125 mg/kg. At 5 mg/kg (effective dose for anxiolytic effect), afobazole did not cause any induction/inhibition effect on CYP2C9 isoenzyme. A multiple increase in afobazole dose was manifested by a moderate induction effect. The maximum induction effect of afobazole was achieved in a dose of 75 mg/kg. At doses above 75 mg/kg, the induction effect of afobazole was less pronounced.

[Pharmacokinetic evaluation of a new prolonged dosage form of afobazole in comparison to commercially available tablets].

Afobazole pharmacokinetics upon oral administration of tablets prepared according to various technologies was studied in rabbits. The main pharmacokinetic parameters were determined.

[In vivo evaluation of the metabolic ratio of CYP2C9 and CYP1A2 drug markers after administration of afobazole in comparison to standard inducers and inhibitors of cytochromes].

The effect of subchronic peroral administration in effective doses of afobazole (5 mg/kg), and cytochrome P450 inductors (rifampicin, 13.4 mg/kg; phenytoin, 10.4 mg/kg) and inhibitors (fluconazole, 35.7 mg/kg; ciprofloxacin, 44.0 mg/kg) on the metabolic ratio (MR) of drugs-markers of CYP2C9 and CYP1A2 activity was studied in rats. Afobazole did not change the MR of compounds metabolized by the P450 isoforms studied. After peroral administration of standard P450 inductors and inhibitors, statistically significant bidirectional effects were identified, which demonstrated the expedience of administering a complex of selected compounds, markers, and CYP2C9 and CYP1A2 activity modificators for comparative evaluation of the effects of new drugs in rats. It is recommended to evaluate the activity of CYP1A2 by determining the MR for one of two caffeine metabolites, paraxanthine or theobromine, and the activity of CYP2C9 by determining the MR of metabolite Exp-3174 to losartan.

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.

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%.

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.

[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.

[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.

[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.

[Comparative pharmacokinetics of dihydroquercetin in rats upon peroral administration of a parent compound and liposomal flamen D].

The pharmacokinetics of dihydroquercetin (DHQ) in the forms of parent substance and a new liposomal formulation (Flamena D) have been studied in rats upon single peroral administration in a dose of 50 mg/kg. DHQ concentration after enzymatic hydrolysis in the blood plasma was determined by HPLC with UV detection. The elimination half-life of DHQ introduced in the form of Flamena D was about T(1/2) = 1.3 h. The relative bioavailability of DHQ after the administration of Flamena D amounted to 159% in comparison to that of the parent substance of DHQ.

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.