Pharmacokinetics and Pharmacodynamics

Journal Information
ISSN / EISSN : 2587-7836 / 2686-8830
Published by: Publishing House OKI (10.37489)
Total articles ≅ 48
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S. S. Boyko, , K. N. Koliasnikova
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-36-41

Abstract:
The review presents the results of studies on the pharmacokinetics, metabolism, and bioavailability of new neurotropic dipeptide cyclo-Lprolilglycine (CPG) and their pharmacological activity. It was shown that the pharmacologically active metabolite of the nootropic drug noopept cyclo-Lprolilglycine (CPG) is an endogenous dipeptide, it is a fragment of the terminal Tripeptide of the insulin-like nerve growth factor IGF-1. Much attention is paid both in Russia and abroad to the development of modified CPG analogues with improved pharmacokinetic properties, enzymatically more stable, better penetrating the BBB, and highly effective when used in micromolar doses. CPG shows neuroprotective activity in ischemic-hypoxic and other brain injuries, in addition, it has a complex of other pharmacological effects and therefore CPG can be considered not only as a potential drug, but also as a basic structure for the development of new neurotropic drugs – analogs of CPG with improved pharmacokinetic properties, greater enzymatic resistance and higher bioavailability for the central nervous system.
G. B. Kolyvanov, P. O. Bochkov, A. A. Litvin, R. V. Shevchenko, А. Л. Подолько,
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-31-35

Abstract:
The pharmacokinetics of a new potential cardioprotective agent ALM-802 was studied in rats after single intravenous and intragastric administration at doses of 10 and 100 mg/kg, respectively. The absolute bioavailability was 4.45 %, which indicates the potential for the development of a dosage form for oral administration
, M. S. Yunusov, I. B. Tsorin, V. V. Barchukov, E. I. Barchukova
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-19-24

Abstract:
The aim of the investigation was the research of the N-deacetyllappaconitine hydrochloride antiarrhythmic properties. It was found that the studied substance was effective on the cardiac arrhythmias model caused by aconitine hydrochloride, but does not act on the models of calciume chlorideinduced arrhythmias and reperfusion ventricular fibrillation. The studied compound is less toxic than the comparison drug lappaconitine hydrobromide and acts in lower doses on the aconitine model of arrhythmias. N-Deacetyllappaconitine hydrochloride appears to be a Class I antiarrhythmic agent according to the Vaughan Williams classification.
P. O. Bochkov, I. P. Khrustova, A. A. Litvin, G. B. Kolyvanov, R. V. Shevchenko,
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-3-10

Abstract:
GIZh-290 is a new derivative of 4-phenylpyrrolidone, based on the structures of racetams that combine anticonvulsant and nootropic effects. The method of high-performance liquid chromatography with mass spectrometric detection was developed and validated for the quantitative determination of a new potential anticonvulsant compound GIZh-290 in rat blood plasma. For the extraction of the analyte, liquid-liquid extraction with diethyl ether was used. The method was validated based on its selectivity, linearity, accuracy, precision, and stability. The linearity of the method was confirmed by a high correlation coefficient of 0.999. The percent recovery of GIZh-290 from blood plasma was 79.2 %. The intra- and inter-batch accuracy were 19.32 and 12.14 %. It was found that blood plasma samples containing GIZh-290 can be stored at ambient temperature during the working day.
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-42-48

Abstract:
Purpose of the study. The pharmacological effects of ornithine are primarily due to its participation in the neutralization of ammonia and in the metabolism of amino acids. To clarify the mechanisms of action of ornithine, a chemoreactom analysis of ornithine aspartate was performed in comparison with S-ademetionine (S-AM) and ursodeoxycholic acid (UDCA). Methods. The effects of the investigated substances on the metabolism of urates (derivatives of uric acid), vasoactivity, vascular structure and cytoprotection were assessed by the method of chemoreactome analysis. Results. It was found that a decrease in blood urate levels is associated with inhibition by ornithine of the urate transporter URAT1 (ornithine – IC50 = 65 nM, S-AM – 1060 nM, UDCA – 94 nM) and xanthine oxidase (ornithine – IC50 = 910 nM, other molecules IC50 = 9655-11040 nM). Among the studied molecules, ornithine was distinguished by the most pronounced vasodilatory properties (probably associated with inhibition of adrenergic receptors: Kd = 35 nM, other molecules – 1108-1428 nM). The highest antidyslipidemic activity was also shown for ornithine (9.4 %) and S-AM (10.2 %), the lowest for UDCA (4.6 %). The antidyslipidemic effect of ornithine is associated with inhibition of endothelial lipase (IC50 = 258 nM for ornithine). The cytoprotective effects of ornithine are associated with an increase in glutathione synthesis, a decrease in the glutamatergic activity of neurons under conditions of glutamate stress, inhibition of prostaglandin D-synthase, and a decrease in the intensity of acute lymphocytic inflammation without immunosuppression. Conclusion. Thus, the results of the ornithine chemoreactom analysis indicate a significant expansion of the spectrum of the pharmacological effects of ornithine, including not only hepatoprotection, but also cardioprotection and nephroprotection.
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-25-30

Abstract:
Relevance. Ethylmethylhydroxypyridine succinate (EMHPS) is a reference domestic drug with pronounced antioxidant and antihypoxic activity. P-Glycoprotein (Pgp) is an ATP-dependent transport protein localized in tissue barriers and protecting cells and organs from the effects of xenobiotics. Being expressed in the blood-brain barrier (BBB), Pgp limits the penetration of drugs and toxic substances into the brain tissue. Aim – to evaluate the effect of EMHPS on the functional activity of Pgp in the BBB of rats in normal conditions and in acute hypoxic hypobaric hypoxia in the experiment. Methods. The studies were carried out on male Wistar rats weighing 200–250 g, which were divided into 4 groups: group 1 (control, n = 30) – intact rats; Group 2 (control of hypoxia, n = 30) – rats, which were simulated hypoxia and before that they were once injected with water for injection; Group 3 (n = 30) – intact animals, which were injected intravenously with EMHPS at a dose of 50 mg / kg body weight; Group 4 (n = 30) – rats, which were injected intravenously with EMHPS at a dose of 50 mg/kg body weight before modeling hypoxia. 30 minutes after injection, animals of groups 2 and 4 were simulated acute hypoxic hypoxia for 30 minutes by ascending to an altitude of 8000 m with an ascent and descent speed of 50 m/s. 3 h after descent animals of groups 2 and 4 and 30 min after intravenous injection in animals of groups 1 and 3, the functional activity of Pgp in the BBB was assessed by the penetration of fexofenadine, a marker substrate of Pgp, into the brain tissue. For this, fexofenadine was injected into the tail vein of rats at a dose of 10 mg/kg of body weight. After 5, 10, 15, 30, 45, 60 minutes after administration, they were euthanized, at least 4 ml of blood was taken from the abdominal aorta into heparinized tubes and the cortex of the frontal lobes of the brain. The concentration of fexofenadine in biosamples was analyzed by HPLC-UV according to original methods. Results. In the course of the study, it was shown that a single intravenous injection of EMHPS at a dose of 50 mg/kg of body weight causes an increase in the content of fexofenadine in the cerebral cortex of rats, which indicates a decrease in the activity of the Pgp transporter protein. Simulation of acute hypoxic hypoxia was also accompanied by an increase in the permeability of the transport protein substrate into the brain tissue. At the same time, the prophylactic administration of EMHPS before hypoxic exposure did not significantly affect the BBB permeability, which remained significantly higher than the control and did not differ from the permeability during isolated hypoxic exposure. Conclusions: EMHPS with a single intravenous injection at a dose of 50 mg/kg body weight reduces the activity of Pgp in the BBB in normal conditions and does not significantly affect the penetration of the transporter substrate – fexofenadine into the brain tissue in acute hypoxic hypoxia
, L. M. Krasnykh, , S. B. Kazanbekov
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-2-11-18

Abstract:
Relevance of the study: The quantification of endogenous substances is an important task in experimental and clinical pharmacology. In the case of working with endogenous compounds, certain difficulties arise. The main one is the impossibility of obtaining the same biomatrix without endogenous compounds for use as standard solutions in the construction of calibration curves. Purpose: The aim of our study was to develop a mathematical methodology for calculating the concentration of endogenous compounds in biological objects measured by chromatography, which allows us to obtain a statistically reliable interval estimation of the concentration of endogenous compounds. Materials and methods: To implement the computational part of the proposed algorithm, the Mathcad engineering calculation program version 15.0 from PTC (Parametric Technology Corporation) is used, which operates under the family of Windows operating systems (XP, 7, Vista, 8). Main results: A mathematical methodology has been developed for calculating the concentration of endogenous compounds in biological objects measured by chromatography, which allows one to obtain a statistically reliable interval estimate of the concentration of endogenous compounds. A feature of this technique is the use of an exclusively analyzed bioobject for quantitative determination of endogenous substances, without the use of so-called “pure” bioobjects for calibration curves, as well as expensive deuterated analogs of markers – substrates of CYP450 isoenzymes and their metabolites. This allows you to maintain the original biomatrix effect when removing the chromatogram. A statistical apparatus is also used to eliminate possible gross errors. To confirm the reliability of the developed method of quantitative determination, the convergence of the results obtained by this method using deuterated standards is established. Conclusions: A mathematical methodology has been developed for calculating the concentration of endogenous compounds in biological objects measured by chromatography, which allows one to obtain a statistically reliable interval estimate of the concentration of endogenous compounds. A feature of this technique is the use of only the analyzed bioobject for quantitative determination of endogenous substances, which allows you to maintain the original biomatrix effect when removing the chromatogram.
I. A. Miroshkina, , I. B. Tsorin, V. N. Stolyaruk, M. B. Vititnova, ,
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-1-30-37

Abstract:
It is known that the alcoholic cardiomyopathy (ACMP) is the main reason for lethality from chronic alcoholism. For ACMP the risk of development of malignant violations of a heart rhythm which result approximately at 40% of such patients is sudden heart death is extremely high. Materials and methods. Experiments were made on the ACMP translational model developed by us which is formed at rats by the end of the 24th week of compulsory reception of 10 % of ethanol solution. For studying the mechanisms which are the responsible of antiarrhythmic action of a fabomotizole dihydrochloride used a complex of morphohistological, electrophysiological and molecular researches. Results. It is shown that against the background of systematic therapy fabomotizole dihydrochloride (15 mg/kg, i.p.) daily within 28 days after 24 weeks of alcoholization, in comparison with alcoholized control the fat dystrophy of a myocardium significantly decreases and the threshold of electric fibrillation of heart ventricles is restored. According to results of molecular researches, a fabomotizole dihydrochloride significantly suppresses revealed in control alkoholized animals the abnormal mRNA expression of key receptor genes and proteins responsible for maintenance in cardiomyocytes of a homeostasis of ions of Ca++ and regulation of their rhythmic activity: regulatory proteins Epac1 (p = 0.021), Epac2 (p = 0.018), CaM (p = 0.00001) and also RyR2 (p = 0.031), IP3R2 (p = 0.006) receptors. Conclusion. The obtained results suggest that antiarrhythmic action of a fabomotizole dihydrochloride in the conditions of ACMP is connected with its ability to suppress abnormal activity of regulatory proteins Epac2 and RyR2, IP3R2 receptors.
I. B. Tsorin, V. V. Barchukov, M. B. Vititnova, A. M. Likhosherstov, ,
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-1-18-22

Abstract:
The investigation purpose. N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethanediamine (ALM-802 compounds) cardioprotective effect has been studied in rat models of subendocardial ischemia caused by isoproterenol and dobutamine. Material and methods. Acute subendocardial myocardial ischemia in anesthetized rats (urethane 1300 mg/kg, i.p.) was caused by infusion of isoproterenol (20 µg/kg/min i.v.) or dobutamine (80 µg/kg/min i.v.). Results. It was shown that in anesthetized rats, isoproterenol and dobutamine caused almost the same ST-segment depression in the II standard ECG lead. The compound ALM-802 (2 mg/kg i.v.), administered 2 minutes before the infusion start of isoproterenol or dobutamine, equally prevented the occurrence of ischemic changes on the ECG. Conclusion. The non-selective beta-adrenomimetic isoproterenol and the selective β1-adrenomimetic dobutamine cause subendocardial ischemia of the same intensity in anesthetized rats. The compound ALM-802 has a pronounced anti-ischemic effect on both models.
P. Yu. Mylnikov, Yu. Tranova, ,
Pharmacokinetics and Pharmacodynamics; https://doi.org/10.37489/2587-7836-2021-1-45-51

Abstract:
Relevance. BCRP is an efflux transporter protein that plays an important role in the pharmacokinetics of a wide range of drugs. The BCRP activity in vitro experiments is assessed by the transport of transporter protein substrates (methotrexate, etc.) across the bilipid membrane of cells overexpressingBCRP, for example, Caco-2 cells. The aim is to develop and validate a method for the quantitative determination of the BCRP substrate, methotrexate, in the transport medium of Caco-2 cells by HPLC-MS/MS. Methods. The work was performed on an Ultimate 3000 HPLC chromatograph (ThermoFisher, USA) with a TSQ Fortis tandem mass-selective detector (ThermoFisher, USA). The conditions of chromatographic analysis were as follows: column UCT Selectra C18 4.6 mm * 100 mm 5um, 100A, Selectra C18 Guard Cartridges SLC-18GDC46-5UM, separation temperature 35 °С, flow rate 0.3 ml/min, injected sample volume - 2 μl, analysis time - 10 min. Used a gradient elution: the ratio of the solution of 0.1 % formic acid and acetonitrile was at 0 min 75 and 25 %; 0.4 min 60 and 40 %; 6 minutes 20 and 80 %; 8 minutes 75 and 25 %. Under these conditions, the retention time of methotrexate is 3.11 minutes. Detection conditions: methotrexate - positive ionization mode, 455.15 m / z → 308.125 m / z, collision energy 22.99 V, source fragmentation 5, CID gas pressure 2 mTorr. The extraction of methotrexate from the transport medium (Hanks solution with 25 mM Hepes and 1% dimethyl sulfoxide) after incubation with Caco-2 cells for 3 h was carried out with a mixture of methanol + water in a ratio of 1: 1. Results. The developed method was validated according to the following parameters: selectivity, linearity, accuracy, precision, limit of quantitative determination, sample transfer, sample stability. The confirmed analytical range of the method was 60 -10,000 nmol / L in the transport medium. Conclusions: a method for the quantitative determination of methotrexate in the transport medium of Caco-2 cells by HPLC-MS / MS was developed and validated.
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