Bykov Vladimir Valer’evich, Bykova Arina Vladimirovna, Leonov Klim Andreevich, Vengerovskii Alexander Isaakovich, Udut Vladimir Vasil’evich
Bykov Vladimir Valer’evich1*, Bykova Arina Vladimirovna1,2, Leonov Klim Andreevich1, Vengerovskii Alexander Isaakovich2, Udut Vladimir Vasil’evich3
1Innovative Pharmacological Research LLC, Tomsk, St. Elizarovs 79/4, Russian Federation.
2Siberian State Medical University, Tomsk, Moskovsky Trakt, 2, Russian Federation.
3Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk, St. Lenin 3, Russian Federation.
Volume - 15,
Issue - 3,
Year - 2022
The goal of the present study: assess the distribution and transmembrane transport of an antiaggregant drug GRS of indolinone series. The distribution of an indolinone derivative in organs, between blood plasma and blood cells was studied in Sprague Dawley rats. A Thermo Scientific Pierce dialysis system was used to study the binding to blood plasma proteins. A MultiScreen Caco-2 test system was used to study the transmembrane transfer of the indolinone derivative. Quantitative assay of GRS was performed by an HPLC/?S method. GRS was shown to pass into the liver, heart and kidneys, and doesn’t pass into the brain and skeletal muscle. The highest GRS accumulation occurs in the liver, the lowest in the kidneys. GRS has low plasma protein binding and its concentration is 1.6 times higher in blood cells than in blood plasma. GRS in 1 mcmol concentration has low cell membrane permeability from apical to basolateral membrane (A-B), increasing the concentration gradient by 10 times leads to a corresponding increase in transport efficiency. In the reverse direction (B-A) GRS permeability is 8.8 times higher, showing its participation in active transport. Pgp inhibitor cyclosporin A considerably decreases the transport efficiency of GRS in B-A direction.
Cite this article:
Bykov Vladimir Valer’evich, Bykova Arina Vladimirovna, Leonov Klim Andreevich, Vengerovskii Alexander Isaakovich, Udut Vladimir Vasil’evich. Distribution and Transmembrane transport as the basis of proper Pharmacodynamics of an Antithrombotic drug – An Indolinone derivative. Research Journal of Pharmacy and Technology. 2022; 15(3):1241-4. doi: 10.52711/0974-360X.2022.00207
Bykov Vladimir Valer’evich, Bykova Arina Vladimirovna, Leonov Klim Andreevich, Vengerovskii Alexander Isaakovich, Udut Vladimir Vasil’evich. Distribution and Transmembrane transport as the basis of proper Pharmacodynamics of an Antithrombotic drug – An Indolinone derivative. Research Journal of Pharmacy and Technology. 2022; 15(3):1241-4. doi: 10.52711/0974-360X.2022.00207 Available on: https://rjptonline.org/AbstractView.aspx?PID=2022-15-3-50
1. Di L et al. Evidence-based approach to assess passive diffusion and carrier-mediated drug transport. Drug Discov Today. 2012; 17(15–16): 905–912.
2. Smith D et al. Passive lipoidal diffusion and carrier-mediated cell uptake are both important mechanisms of membrane permeation in drug disposition. Mol Pharm. 2014; 11(6):1727–1738.
3. Sugano K et al. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. 2010; 9(8): 597–614.
4. Kell DB et al. Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Discov Today. 2011; 16(15-16): 704–714.
5. Scott DO et al. Passive drug permeation through membranes and cellular distribution. Pharmacol Res. 2016; 117: 94–102.
6. Kaufmann AM, Krise JP. Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications. J Pharm Sci. 2007; 96(4): 729–746.
7. Swietach P et al. PLoS One. 2012; 7(4): e35949.
8. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2001; 71(3): 115–121.
9. van Steeg TJ et al. Influence of plasma protein binding on pharmacodynamics: Estimation of in vivo receptor affinities of beta blockers using a new mechanism-based PK-PD modelling approach. J Pharm Sci. 2009; 98(10): 3816–3828.
10. Haller C. Hypoalbuminemia in renal failure: pathogenesis and therapeutic considerations. Kidney Blood Press Res. 2005; 28(5-6): 307–310.
11. Joynt GM et al. The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients. J Antimicrob Chemother. 2001; 47(4): 421–429.
12. Granik VG et al. Exogenous nitric oxide donors and inhibitors of its formation (the chemical aspects). Russ Chem Rev. 1997; 66(8): 792–807.
13. V.V. Bykov et al. Effects on thrombocytic hemostasis of a new derivate indolinone. 2019; BJMS Vol. 18: 574-576.
14. European Medicines Agency. Guideline on Bioanalytical Method Validation. Available from: URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf.
15. FDA. Bioanalytical Method Validation. Guidance for Industry. Available from: URL: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioanalytical-method-validation-guidance-industry
16. Bykov VV et al. Metabolism of a New Antiaggregant, Indolinone Derivative. Bull Exp Biol Med. 2020; 168(6): 739–742.
17. Mahamadi A et al. Potential psychoactive indole derivatives II: Synthesis of 5‐alkoxyindolines via reduction of 5‐alkoxy‐2‐indolinones. J Pharm Sci. 1973; 62(3): 490-492. https://doi.org/10.1002/jps.2600620332.
18. Cohen S. The Beyond Within: The LSD Story. Atheneum, New York. 1964.
19. Kul D et al. Electroanalytical characteristics of antipsychotic drug ziprasidone and its determination in pharmaceuticals and serum samples on solid electrodes. Talanta. 2008; 82(1): 286–295. doi: 10.1016/j.talanta.2010.04.036.
20. Passie T et al. The Pharmacology of Lysergic Acid Diethylamide: A Review. CNS Neurosci Ther. 2008; 14(4): 295–314. doi:10.1111/j.1755-5949.2008.00059.x.