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Simulation of the Level of Prostaglandins in Open Systems under the Action of Nonsteroidal Anti-Inflammatory Drugs

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Abstract

Modeling the flow and level of prostaglandins in open systems under the action of prostaglandin H synthase (PGHS) inhibitors (nonsteroidal anti-inflammatory drugs, NSAIDs) was carried out. These open systems included a steady PGHS input, fast inactivation of PGHS during the reaction, degradation of all PGHS forms, conversion of prostaglandin (PG) to biologically inactive substances, and various types of delivery of inhibitors and substrate (arachidonic acid, AA). A slow reversible inhibitor of PGHS (indomethacin) and a slow irreversible inhibitor of PGHS (aspirin) were considered as inhibitors. The explicit analytical expressions for flows and concentrations in steady state and transient mode were obtained. In steady state the dependences of flow and level of PG on the concentration of AA were described by the Michaelis–Menten-type equation. The values of the maximum flows, maximum levels, and Michaelis constant in these equations are inversely proportional to the constant of inactivation of the enzyme during the reaction. In the closed systems, slow PGHS inhibitors are manifested as non-competitive with respect to AA, but in open systems, their behavior is fully competitive with respect to AA, so the presence of inhibitor increases the range of changes of PG level under the change of AA concentration. The reversible inhibitor (indomethacin), in contrast to the irreversible inhibitor (aspirin), in transient mode has been shown to manifest itself as the repository for the active enzyme because of the formation of enzyme-inhibitory complexes. The system disturbance under the rapid increase of indomethacin concentration leads to the biphasic change of the PG level: after the initial rapid decrease it increases gradually to the new steady state. In the presence of indomethacin, the system disturbance under the rapid increase of AA concentration leads to the release of the enzyme from enzyme-inhibitory complexes, and the PG level for a certain period significantly increases compared with the absence of inhibitor. The results of modeling of the regulation of the level of prostaglandins in different states of the open systems undoubtedly need to be used in the study of NSAIDs in vivo.

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ACKNOWLEDGMENTS

The study was carried out using the equipment purchased at the expense of the Development Program of Moscow State University and equipment of the Center for Collective Use of Ultra-High Performance Computing Resources of Lomonosov Moscow State University.

Funding

The work was supported by the Russian Foundation for Basic Research (project no. 19-04-01150а).

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Authors and Affiliations

  1. International Biotechnological Center, Lomonosov Moscow State University, 119991, Moscow, Russia

    A. V. Krivoshey & P. V. Vrzheshch

  2. Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia

    A. V. Krivoshey, A. A. Efremov, E. K. Matveishina, V. V. Panova & P. V. Vrzheshch

  3. Research Center of Biotechnology, Institute of Bioengineering, Russian Academy of Sciences, 119071, Moscow, Russia

    E. K. Matveishina

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  1. A. V. Krivoshey
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  2. A. A. Efremov
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Correspondence to P. V. Vrzheshch.

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The article contains no studies involving animals or humans as subjects of the study.

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Translated by N. Onishchenko

Abbreviations: NSAID, nonsteroidal anti-inflammatory drugs; AA, arachidonic acid; COX, cyclooxygenase; DEDTC, sodium diethyldithiocarbamate; PG, prostaglandin; PGHS, prostaglandin H synthase.

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Krivoshey, A.V., Efremov, A.A., Matveishina, E.K. et al. Simulation of the Level of Prostaglandins in Open Systems under the Action of Nonsteroidal Anti-Inflammatory Drugs. Russ J Bioorg Chem 47, 1051–1059 (2021). https://doi.org/10.1134/S1068162021050289

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