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.

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.

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.

[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.

[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.

[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.

[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).

[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.

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.

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%).

[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.

[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.

[Comparative pharmacokinetics and relative bioavailability of magnesium-containing drugs].

Pharmacokinetics of magnesium ions after single peroral administration of Magnelis B6 and Magne B6 coated tablets (magnesium dose, 48 mg) was studied in rabbits. In the blood plasma, the level of magnesium ions was very low compared to the endogenous level, which did not allow the drug bioavailability to be reliable evaluated. At the same time, the level of magnesium ions was reliable determined in the daily urine of test animals.

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.

[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.

[Therapeutic effect and pharmacokinetics of transdermal phenazepam preparation in patients with different anxiety disorders].

Clinical investigation of a transdermal phenazepam preparation (phenapercuten) in patients diagnosed with different anxiety disorders revealed an original therapeutic action of the new drug, which included both a selective anxiolytic effect and an activating (antiasthenic) component in the absence of undesired sedative and miorelaxant properties. It is shown that the specific action of phenapercuten is related to features of the pharmacokinetic profile of this transdermal drug that is characterized by a low levels of active compound in the blood plasma and by the absence of peak concentrations. TTS Phenapercuten was most effective in patients with anxiety disorders of simple structure.

Excretion of afobazole and its metabolites with urine and feces in rats.

The amount of afobazole and identified metabolites was measured in the urine and feces of rats after intraperitoneal and peroral administration of the drug in a dose of 25 mg/kg. Over 1 day after intraperitoneal or peroral treatment with afobazole, urine and feces contained 0.1% initial compound (from administered dose) and 42.

[Afobazole metabolism in rats].

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.

Experimental study of the pharmacokinetics of a tryptophan-containing dipeptide GB-115.

Pharmacokinetics of an original compound GB-115 (N-phenylhexanoylglycyltryptophan) synthesized on the basis of the structure of endogenous tetrapeptide cholecystokinin-4 was studied by means of high-performance liquid chromatography. Pharmacokinetic parameters were calculated after intravenous and peroral administration of GB-115. Our results indicate that this dipeptide is resistant to peptidases.