Study of Pharmacokietics of tritium-labeled Kagocel

DOI: https://doi.org/10.29296/25419218-2019-08-08
Issue: 
8
Year: 
2019

A.A. Andreev-Andrievsky, PhD(1, 2, 3); A.S. Popova, PhD(1); E.A. Lagereva(1, 2); M.A. Mashkin(1, 2); Professor B.A. Rudoy, PhD(4); Yu.G. Kazaishvili, PhD(5); V.S. Shchervbakova, PhD(5) 1-LLC «Research Institute of Mitoengineering, Moscow State University»; 2-Faculty of Biology, M.V. Lomonosov Moscow State University; 3-State Research Center of the Russian Federation – Institute of Biomedical Problems, Russian Academy of Sciences, Moscow; 4-LLC «Nearmedic Plus», Moscow; 5LLC «Nearmedik Pharma», Moscow

Introduction. The pharmaceutical substance Kagocel is the active substance of the drug of the same name, which is used to treat viral infections. The method using tritium as a radioactive label is most appropriate to study the pharmacokinetics of this high-polymer compound in animal experiments. Objective: to perfect a bioanalytical procedure for detecting kagocel in animals and determining the main features of the pharmacokinetics of this polymer substance. Material and methods. Pharmacokinetic studies were conducted using the tritium-labeled Kagocel substance in Wistar rats. The investigation quantified the level of kagocel in the blood, tissues, and excreta of the animals. Results. The possibility of studying the pharmacokinetics of kagocel, by using the solutions of tritium-labelled substance was experimentally confirmed. The investigators determined the main pharmacokinetic parameters that were used to establish that kagocel is the typical polymer substance with a relatively low (13 –15%) absolute bioavailability when administered orally. Kagocel was characterized by its long (about 2-day) half-life and without substantial accumulation in organs and tissues. The investigators also established some methodological features of using tritium-labeled modified polysaccharides, which should be taken into account when validating the bioanalytical procedures for controlling the distribution and excretion of such products. Conclusion. The methodological approaches applied in this investigation allow quantification of the level of tritium-labeled kagocel in biological matrices. Additional studies are needed to clarify a number of parameters that more fully characterize the ADME processes of the polymer kagocel

Keywords: 
kagocel
polymer
pharmacokinetics
tritium
label

References: 
  1. Sologub T.V., Tsvetkov V.V. Kagotsel v terapii grippa i ostryh respiratornyh virusnyh infektsij: analiz i sistematizatsija dannyh po rezul'tatam doklinicheskih i klinicheskih issledovanij. Terapevticheskij arhiv. 2017; 89(8): 113–119. [Sologub T. V. and Tsvetkov V. V. Kagocel in the therapy of influenza and acute respiratory viral infections: data analysis and systematization from the results of preclinical and clinical trials. Terapevticheskii arkhiv, 2017; Vol. 89(8): 113-119. (in Russian)].
  2. 2. Kagotsel v pediatrii. K voprosu o reproduktivnoj bezopasnosti: Sbornik statej i materialov. Pod obsch. red. chl-korr. RAN T.A. Gus'kovoj. Moskva: OOO «Izdatel'stvo «Meditsinskoe informatsionnoe agenstvo», 2018: 112. [Kagocel in pediatrics. On the issue of reproductive safety: collected articles. Ed. by T.A. Guskova. Moscow, 2018. (in Russian)].
  3. 3. Lockley W.J.S., McEwen A., Cooke R. Tritium: a coming of age for drug discovery and development ADME studies. Journal of labeled compounds and radiopharmaceuticals, 2012; Vol. 55 (7): 235–257.
  4. 4. Atzrodt J., Derdau V., Kerr W.J., Reid M. Deuterium and tritium labelled compounds: applications in the life sciences. Angewandte chemie international edition, 2018; Vol. 57 (7): 1758–1784.
  5. 5. Pointurier F., Baglan N., Alanic G., Chiappini, R. Determination of organically bound tritium background level in biological samples from a wide area in the south-west of France. Journal of environmental radioactivity, 2003; Vol. 68 (2): 171–189.
  6. 6. Baumgärtner F., Donhaerl W. Non-exchangeable organically bound tritium (OBT): its real nature. Analytical and bioanalytical chemistry, 2004; Vol. 379(2): 204–209.
  7. 7. Kim S.B., Baglan N., Davis P.A. Current understanding of organically bound tritium (OBT) in the environment. Journal of environmental radioactivity, 2013; Vol. 126: 83–91.
  8. 8. Sang-Bog Kim, Roche J. Empirical insights and considerations for the OBT inter-laboratory comparison of environmental samples. Journal of environmental radioactivity, 2013; Vol. 122: 79–85.
  9. 9. Sidorov G.V., Kazaishvili Ju.G., Rudoj B.A. Sintez polimernoj substantsii «Kagotsel», mechennoj tritiem: metod tverdofaznogo kataliticheskogo geterogennogo izotopnogo obmena. Farmatsija. 2018; 67 (8): 16–21. [Sidorov G.V., Kazaishvili Yu.G., Rudoy B.A. Synthesis of tritium-labeled polymeric Kagocel substance: solid-phase catalytic heterogeneous isotope exchange method. Farmatsiya, 2018; Vol. 67 (8): 16–21. https//doi.org/10/29296/25419218-2018-08-03 (in Russian)].
  10. 10. Badun G.A., Chernysheva M.G., Kazaishvili Ju.G., Rudoj B.A. Sintez polimernoj substantsii «Kagotsel», mechennoj tritiem: metod termicheskoj aktivatsii tritija. Farmatsija, 2018; 67 (7): 14–20. [Badun G.A., Chernisheva M.G., Kazaishvili Yu.G., Rudoy B.A. Synthesis of tritium-labelled polymeric kagocel substance: tritium thermal activation method .Farmatsiya, 2018; Vol. 67 (7): 14–20. https//doi.org/10/29296/25419218-2018-07-03 (in Russian)]
  11. 11. Krimsky M., Dagan A., Aptekar L. et al. Assessment of intestinal permeability in rats by permeation of inulin-fluorescein. Journal of basic and clinical physiology and pharmacology, 2000; Vol. 11 (2): 143-154.
  12. 12. Takeda H., Kasida Y. Biological behavior of tritium after administration of tritiated water in the rat. Journal of radiation research, 1979; Vol. 20 (2): 174–185.
  13. 13. Pantzar N., Westrom B.R., Luts A., Lundin S. Regional small-intestinal permeability in vitro to different-sized dextrans and proteins in the rat. Scand. J. Gastroenterol., 1993; Vol. 28: 205–211.
  14. 14. Yuasa H., Kuno C., Watanabe J. Comparative assessment of D-xylose absorption between small intestine and large intestine. The journal of pharmacy and pharmacology, 1997; Vol. 49 (1): 26–29.
  15. 15. Han Y., Li X., Chen H., Hu X., Luo Y. et al. Real-time imaging of endocytosis and intracellular trafficking of semiconducting polymer dots. ACS applied materials & interfaces, 2017; Vol. 9 (25): 21200–21208.
  16. 16. Giebisch G., Lauson H.D., Pitts R.F. Renal excretion and volume of distribution of various dextrans. American journal of physiology, 1954; Vol. 178(1): 168–176.
  17. 17. Hanngren A., Hansson E., Ullberg S., Aberg B. Fate of injected dextran labeled with tritium in mice. Nature, 1959; Vol. 184 (4683): 373–374.
  18. 18. Lawrence M.G., Altenburg M.K., Sanford R., et al. Permeation of macromolecules into the renal glomelular basement membrane and capture by the tubules. Proceedings of the National Academy of Sciences, 2017; Vol. 114 (11): 2958–2963.
  19. 19. Shaffer C.L., Gunduz M., Thornburgh B.A. et al. Tritiated compound to elucidate its preclinical metabolic and excretory pathways in vivo: exploring tritium exchange risk. Drug metabolism and disposition, 2006; Vol. 34 (9): 1615–1623.