Evaluation of the stability of furosemide in tablet form during six-month storage in spaceflight and peculiarities of its pharmacokinetics and pharmacodynamics under conditions of anti-orthostatic hypokinesia

Alexey V. Polyakov; Andreу A. Svistunov; Svetlana N. Kondratenko; Irina V. Kovachevich; Lyudmila G. Repenkovа; Marina I. Savelyevа; Evgenia V. Shikh; Victor B. Noskov

doi:10.1515/dmpt-2021-0149

Article

Evaluation of the stability of furosemide in tablet form during six-month storage in spaceflight and peculiarities of its pharmacokinetics and pharmacodynamics under conditions of anti-orthostatic hypokinesia

Alexey V. Polyakov , Andreу A. Svistunov , Svetlana N. Kondratenko , Irina V. Kovachevich , Lyudmila G. Repenkovа , Marina I. Savelyevа , Evgenia V. Shikh and Victor B. Noskov

Published/Copyright: February 24, 2022

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From the journal Drug Metabolism and Personalized Therapy Volume 37 Issue 3

Abstract

Objectives

The present study investigated the stability of furosemide under space-flight conditions on board the International Space Station, as well as its pharmacokinetics and pharmacodynamics under conditions simulating exposure to some space-flight factors.

Methods

Quantitative analysis of furosemide tablets by HPLC was performed before spaceflight (background), then after six months storage under normal ground conditions (control) and under spaceflight conditions (SF). The pharmacokinetics and pharmacodynamics of furosemide were studied in six healthy volunteers after a single oral dose of 40 mg under normal conditions (background) and under anti-orthostatic hypokinesia (ANOH).

Results

Quantitative content of furosemide in tablets before SF was 40.19 ± 0.28 mg (100.47 ± 0.71%), after 6 months storage: under normal conditions (control) – 39.9 ± 0.39 mg (99.73 ± 0.98%), under SF – 39.24 ± 0.72 mg (98.11 ± 1.80%), which was within the prescribed limits. Studying basic hemodynamic parameters showed that in ANOH conditions 6 h after furosemide administration there was a statistically significant increase of the stroke volume (SV) (+36.5 Δ%), a tendency for increasing of the stroke index (SI) (+36.5 Δ%) and decreasing of the total peripheral resistance (TPR) (−21.9 Δ%) compared to baseline study.

Conclusions

It has been established that various factors of space flight (overloading, excessive vibration, microgravity, etc.) do not negatively influence the stability of furosemide in tablet form during storage for 6 months on board the International Space Station.

Keywords: anti-orthostatic hypokinesia; furosemide; hemodynamics; pharmacodynamics; pharmacokinetics; spaceflight; stability

Corresponding author: Marina I. Savelyevа, Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia, Moscow, Russian Federation, E-mail: marinasavelyeva@mail.ru

Research funding: None declared.
Author contributions: Alexey V. Polyakov has substantial contributions to the conception and design of data for the work; and revising it critically for important intellectual content; and final approval of the version to be published; and integrity of any part of the work are appropriately investigated and resolved because he was a main scientific leader of research study on the stability of furosemide tablets in space flight and ground condition. Andreу A. Svistunov has substantial contributions to the acquisition and interpretation of data for the work (he was responsible for the scientific leadership and organization of pharmacokinetic studies of furosemide) and revising it critically for important intellectual content and final approval of the version to be published and agreement to be accountable for all aspects of the work. Svetlana N. Kondratenko has substantial contributions to the quantitative analysis of furosemide in the dosage form and biological fluids of volunteers, pharmacokinetic calculations, interpretation of data for the work, and drafting the article; and final approval of the version to be published; and agreement to be accountable for all aspects of the work. Irina V. Kovachevich has substantial contributions to the conception and design of data for the work because she was a scientific supervisor of drug research in the conditions of the Head-down Bed Rest analog study (HDBR); and revising the work critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work. Lyudmila G. Repenkovа has substantial contributions to the analysis of the research study of hemodynamics after taking furosemide; and revising the work critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work. Marina I. Savelyevа has substantial contributions to the interpretation of data for the work and statistical analysis of research results, and drafting the work (writing an article in English); and final approval of the version to be published; and agreement to be accountable for all aspects of the work. Evgenia V. Shih has substantial contributions to the conception and design of data for the work; and revising it critically for important intellectual content; and final approval of the version to be published; and integrity of any part of the work are appropriately investigated and resolved. Victor B. Noskov has substantial contributions to the conception and design of data for the work (organization of studies of diuretics); and revising it critically for important intellectual content; and final approval of the version to be published; and integrity of any part of the work are appropriately investigated and resolved. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Written informed consent was obtained from all participants in the study before the beginning of any procedures.
Ethical approval: Clinical studies of the research were conducted in accordance with all the relevant Russian national regulations, institutional policies, and in accordance with the principles of the Declaration of the World Medical Association (Edinburgh, 2000), and in accordance with the tenets of the Helsinki Declaration. The research program was approved by the Academic Council of the Institute in 1996 in accordance with the approved regulations for conducting clinical and experimental research at the Institute. However, the documentation was not preserved due to the transfer of the Institute to another subordination (from the Ministry of Health to the Russian Academy of Sciences).

References

1. Blue, RS, Bayuse, TM, Daniels, VR, Wotring, VE, Suresh, R, Mulcahy, RA, et al.. Supplying a pharmacy for NASA exploration spaceflight: challenges and current understanding. NPJ Microgravity 2019;5:14. https://doi.org/10.1038/s41526-019-0075-2.Search in Google Scholar PubMed PubMed Central

2. Blue, RS, Chancellor, JC, Antonsen, EL, Bayuse, TM, Daniels, VR, Wotring, VE. Limitations in predicting radiation-induced pharmaceutical instability during long-duration spaceflight. NPJ Microgravity 2019;5:15. https://doi.org/10.1038/s41526-019-0076-1.Search in Google Scholar PubMed PubMed Central

3. Braddock, M. Ergonomic challenges for astronauts during space travel and the need for space medicine. J Ergon 2017;7:221. https://doi.org/10.4172/2165-7556.1000221.Search in Google Scholar

4. Eyal, S. How do the pharmacokinetics of drugs change in astronauts in space? Expert Opin Drug Metab Toxicol 2020;16:353–6. https://doi.org/10.1080/17425255.2020.1746763.Search in Google Scholar PubMed

5. Kast, J, Yu, Y, Seubert, CN, Wotring, VE, Derendorf, H. Drugs in space: pharmacokinetics and pharmacodynamics in astronauts. Eur J Pharm Sci 2017;109S:S2–S8. https://doi.org/10.1016/j.ejps.2017.05.025.Search in Google Scholar PubMed

6. Iosim, S, MacKay, M, Westover, C, Mason, CE. Translating current biomedical therapies for long duration, deep space missions. Precis Clin Med 2019;2:259–69. https://doi.org/10.1093/pcmedi/pbz022.Search in Google Scholar PubMed PubMed Central

7. Eyal, S, Derendorf, H. Medications in space: in search of a pharmacologist’s guide to the galaxy. Pharm Res 2019;36:148. https://doi.org/10.1007/s11095-019-2679-3.Search in Google Scholar PubMed

8. Benson, S, Cable, G, Workman, L. Challenges in anaesthesia during space exploration missions. J Aust Soc Aerosp Med 2019;11:1–10. https://doi.org/10.21307/asam-2019-002.Search in Google Scholar

9. Chancellor, JC, Blue, RS, Cengel, KA, Auñón-Chancellor, SM, Rubins, KH, Katzgraber, HG, et al.. Limitations in predicting the space radiation health risk for exploration astronauts. NPJ Microgravity 2018;4:8. https://doi.org/10.1038/s41526-018-0043-2.Search in Google Scholar PubMed PubMed Central

10. Wotring, V. Spaceflight pharmacology. In: Barratt, M, Baker, E, Pool, S, editors. Principles of clinical medicine for space flight. New York, NY: Springer; 2019. pp. 815–40. https://doi.org/10.1007/978-1-4939-9889-0_27.Search in Google Scholar

11. Du, B, Daniels, VR, Vaksman, Z, Boyd, JL, Crady, C, Putcha, L. Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS J 2011;13:299–308. https://doi.org/10.1208/s12248-011-9270-0.Search in Google Scholar

12. Wotring, VE. Absorption. In: Space Pharmacology. SpringerBriefs in Space Development. Boston, MA: Springer; 2012. https://doi.org/10.1007/978-1-4614-3396-5_2.Search in Google Scholar

13. Kohn, FPM, Hauslage, J. The gravity dependence of pharmacodynamics: the integration of lidocaine into membranes in microgravity. NPJ Microgravity 2019;5:5. https://doi.org/10.1038/s41526-019-0064-5.Search in Google Scholar

14. Grigoriev, AI. General mechanisms of the effects of weightlessness on the human. In: Bonting, SL, editor. Advan. in space biology and medicine. London: JAI Press Inc.; 1992, vol 2. pp. 1–42. https://doi.org/10.1016/s1569-2574(08)60016-7.Search in Google Scholar

15. Cintron, NM, Lane, HW, Leach, CS. Metabolic consequences of fluid shifts induced by microgravity. Physiologist 1990;33(1 Suppl):S16-9. https://pubmed.ncbi.nlm.nih.gov/2196599/.Search in Google Scholar

16. Kovachevich, IV, Kondratenko, SN, Starodubshev, AK, Repenkova, LG. Pharmacokinetics of tablet and capsule formulations of acetaminophen in conditions of prolonged space flight. Pharm Chem J 2009;43:130–3. https://doi.org/10.1007/s11094-009-0255-6.Search in Google Scholar

17. Tietze, KJ, Putcha, L. Factors affecting drug bioavailability in space. J Clin Pharmacol 1994;6:671–6. https://doi.org/10.1002/j.1552-4604.1994.tb02022.x.Search in Google Scholar PubMed

18. Goncharov, IB, Kovachevich, IV. The system of rendering medical aid to astronauts. In: Orbital station «Mir»: Space biology and medicine. V.1. Medical support of long-term missions. Moscow: State Scientific Center of the Russian Federation - Institute of Medical and Biological Problems of the Russian Academy of Sciences; 2001.Search in Google Scholar

19. Ramenskaya, GV, Kondratenko, SN, Krasnykh, LM. Methods of quantitative determination of drugs in the blood plasma of patients by high performance liquid chromatography. In: Clinical pharmacokinetics: theoretical, applied and analytical aspects. Moscow: GEOTAR-Media; 2009.Search in Google Scholar

20. State Pharmacopoeia of the Russian Federation. The XIV edition. Moscow: Ministry of Health of the Russian Federation; 2018.Search in Google Scholar

21. Ram, VR, Dave, PN, Joshi, HS. Development and validation of a stability-indicating HPLC assay method for simultaneous determination of spironolactone and furosemide in tablet formulation. J Chromatogr Sci 2012;50:721–6. https://doi.org/10.1093/chromsci/bms062.Search in Google Scholar PubMed

22. Bondareva, IB, Budanov, SV, Bunyatyan, ND, Zherdev, VP, Kolyvanov, GB, Kondratenko, SN, et al.. Bioequivalence assessment of drugs. Moscow: Scientific Center Expertise of Medical Applications; 2008.Search in Google Scholar

23. Miroshnichenko, II, Tyulyaev, II, Zuev, AP. Bioavailability of drugs. Moscow: Gramotey; 2003.Search in Google Scholar

24. Agafonov, AA, Piotrovskii, VK. M-IND software for evaluation of pharmacokinetic system parameters by the model-independent method of statistical moments. Khim Farm Zh 1991;25:16–9.10.1007/BF03036253Search in Google Scholar

25. Sergienko, VI, Jelliffe, R, Bondareva, IB. Applied pharmacokinetics: basic provisions and clinical application. Moscow: RAMS Publishing House; 2003.Search in Google Scholar

26. Luts, RJ, Dedrick, RL, Matthews, HB, Eling, TE, Anderson, MW. A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. Drug Metab Disp 1977;5:386–96. https://pubmed.ncbi.nlm.nih.gov/19218/.Search in Google Scholar

27. United States Pharmacopeia and National Formulary (USP40-NF35). United States Pharmacopeial Convention, Rockville, MD, 2016.Search in Google Scholar

28. Hanna, GM, Lau-Cam, CA. Stability-indicating proton nuclear magnetic resonance spectroscopic assay method for furosemide in tablets and injections. J AOAC Int 1993;76:526–30. https://doi.org/10.1093/jaoac/76.3.526.Search in Google Scholar

29. Carda-Broch, S, Esteve-Romero, J, García-Alvarez-Coque, MC. Furosemide assay in pharmaceuticals by micellar liquid chromatography: study of the stability of the drug. J Pharm Biomed Anal 2000;23:803–17. https://doi.org/10.1016/s0731-7085(00)00378-2.Search in Google Scholar

30. Chuong, MC, Prasad, D, Leduc, B, Du, B, Putcha, L. Stability of vitamin B complex in multivitamin and multimineral supplement tablets after space flight. J Pharm Biomed Anal 2011;5:1197–200. https://doi.org/10.1016/j.jpba.2011.03.030.Search in Google Scholar PubMed

31. Gazenko, OG, Grigoriev, AI, Natochin, YuV. Water-salt homeostasis and space flight. Moscow: Nauka; 1986.Search in Google Scholar

32. Polyakov, AV, Svistunov, AA, Kondratenko, SN, Kovachevich, IV, Repenkova, LG, Savelyeva, MI, et al.. Peculiarities of pharmacokinetics and bioavailability of some cardiovascular drugs under conditions of antiorthostatic hypokinesia. Bull Exp Biol Med 2020;168:465–9. https://doi.org/10.1007/s10517-020-04732-w.Search in Google Scholar PubMed

33. Hammarlund-Udenaes, M, Benet, LZ. Furosemide pharmacokinetics and pharmacodynamics in health and disease–an update. J Pharmacokinet Biopharm 1989;17:1–46. https://doi.org/10.1007/bf01059086.Search in Google Scholar

34. Kelly, MR, Cutler, RE, Forrey, AW, Kimpel, BM. Pharmacokinetics of orally administered furosemide. Clin Pharmacol Ther 1974;15:178–86. https://doi.org/10.1002/cpt1974152178.Search in Google Scholar

35. Fritsch, JM, Rea, RF, Eckberg, DL. Carotid baroreflex resetting during drug-induced arterial pressure changes in humans. Am J Physiol 1989;256 (2 Pt 2):R549–553. https://doi.org/10.1152/ajpregu.1989.256.2.R549.Search in Google Scholar PubMed

36. Fritsch-Yelle, JM, Charles, JB, Jones, MM, Beightol, LA, Eckberg, DL. Spaceflight alters autonomic regulation of arterial pressure in humans. J Appl Physiol 1994;77:1776–83. https://doi.org/10.1152/jappl.1994.77.4.1776.Search in Google Scholar PubMed

37. Noskov, VB. The effect of body position and diuretic administration on the water-salt status and kidney activity. Hum Physiol 1982;8:638.Search in Google Scholar

Received: 2021-06-07

Accepted: 2021-11-28

Published Online: 2022-02-24

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Articles in the same Issue

https://doi.org/10.1515/dmpt-2021-0149

Keywords for this article

anti-orthostatic hypokinesia; furosemide; hemodynamics; pharmacodynamics; pharmacokinetics; spaceflight; stability