Abstract
Objectives
To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions.
Methods
The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied.
Results
The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (−54 Δ%), furosemide (−20 Δ%), propranolol (−8 Δ%), and acetaminophen (−9 Δ%), but a statistically significant increase in Vz was found for etacizine (+39 Δ%); there was an increasing trend in Clt for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (−22, −23 and −9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (−5 and −12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (−19 and −20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC0-∞ (−57 Δ%), Cmax (−53 Δ%), relative bioavailability of acetaminophen (−52 Δ%) and a sharp increase in Clt (+147 Δ%), Tmax (+131 Δ%) as well as a trend towards a significant decrease in T1/2 (−53 Δ%), MRT (−36 Δ%) and a moderate increase in Vz (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies.
Conclusions
The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.
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Research funding: None declared.
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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 spaceflight 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 acetominophen) 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 all drugs of the study 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 under antiorthostatic hypokinesia (ANOH); 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 all study drugs; 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. Lidiya Y. Badriddinova has substantial contributions to the conception and design of data for the work especially for acetominophen study; 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.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Written informed consent was obtained from all participants in the study before the beginning of any procedures.
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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).
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