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%.

[Pharmacokinetics of noopept and its active metabolite cycloprolyl glycine in rats]. / Farmakokinetika noopepta i ego aktivnogo metabolita tsikloprolilglitsina u krys.

The study of the pharmacokinetics of new drugs and the identification of active metabolites is a necessary step for effective and safe use in the clinical practice. It is especially important for peptide drugs due to their enzymatic instability, low bioavailability and poor permeability through the blood-brain barrier (BBB). The role of endogenous neuropeptides containing cyclic amino acids, proline, pyroglutamic acid, and glycine, in the regulation of memory processes is known as terminal peptide fragments. The development of nootropic drugs based on natural neuropeptides with high pharmacological activity and improved pharmacokinetic properties (enzymatic stability, high bioavailability, and good permeability through the BBB) is an important problem of modern neuropsychopharmacology. Developed drugs - representing short (di- and tri-) peptides appear to meet these requirements. In the Zakusov Research Institute of Pharmacology a nootropic agent noopept (N-phenylacetyl-prolyl-L-glycine ethyl ester), was developed and introduced into medical practice, studies of its pharmacokinetics in ratsrevealed that the noopept metabolite found in the rat plasma and brain, cyclo-prolyl-L-glycine (CPG), differed significantly in its pharmacokinetic parameters from noopept, but at the same time it had similar noopept multi-component spectrum of pharmacological action, namely the influence on higher integrative functions of memory.

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%.

[EXPERIMENTAL PHARMACOKINETICS AND PHARMACODYNAMICS OF GB-115 DIPEPTIDE ANXIOLYTIC SUBSTANCES].

Pharmacokinetics and pharmacological activity of GB-115 dipeptide anxiolytic after oral administration in the form of crystalline and micronized substances was studied in albino male rats. In contrast to crystalline, the micronized substance exhibited better pharmacokinetic parameters and higher bioavailability. In the "elevated plus maze" test, GB-115 in micronized form at a dose 0.3 mg/kg demonstrated pronounced anxiolytic properties during prolonged period as compared to crystalline substance at the same dose. The obtained data allow the micronized substance of GB-115 to be recommended for inclusion in pharmaceutical composition of new dipeptide anxiolytic drug formulations.

[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.

[Pharmacokinetics of three peroral dosage forms of new dipeptide anxiolytic drug GB-115].

Comparative analysis of the pharmacokinetics and bioequivalence of a new dipeptide anxiolytic compound GB-115 in three drug forms for peroral administration, developed in the experimental technology department of the Institute of pharmacology RAMS, was carried out. Three drug forms of GB-115 and a micronized substance of this compound were different in composition and technology of production. As a result of the investigations of GB-115 pharmacokinetics, drug form No. 2 (with a relative bioequivalence of 192%) showed advantages in comparison to the micronized parent substance and two other drug forms (bioequivalence, 53 and 117%) and can be recommended for further pharmacological studies.

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.

[Evaluation of pharmacokinetic interaction of aphobazole with CYP1A2 drug-substrate in experiments].

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.

[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.