The pharmacokinetics of acetaminophen in two medicinal forms, tablets and capsules, have been studied in healthy volunteers after single peroral administration at a dose of 500 mg under usual living conditions and during long-term space flight. The rate of drug absorption from tablets decreases significantly whereas the relative bioavailability increases substantially under microgravity conditions (compared with usual conditions). For the encapsulated medicinal form, the time of absorption decreases statistically reliably and the half-elimination time, the average retention time, and the distribution volume increase considerably whereas the bioavailability changes insignificantly.The onset of a clinical effect and its strength and duration through any administration pathway depend on the bioavailability of the drug. The effects on the pharmacokinetics and bioavailability of acetaminophen of such factors as the age [1, 2] and sex [1, 3] of patients, the excess of body mass [3], the condition of gastro-intestinal tract peristalsis, simultaneous administration with various foods [4,5], and type of motor activity (including prolonged anti-orthostatic hypokinesia) and sleep [6,7] are currently widely studied.Factors such as weightlessness, changes of water-salt balance, mineral saturation of bone, hematological changes, reduction of immunological reactivity, functional changes of neuropsychic status and gastro-intestinal system, etc. are known to have a negative effect on the human organism during long-term space flight. However, the actual trends in the pharmacokinetics of various drugs (including acetaminophen) during long-term space flight are practically unstudied and are very critical because the probability of developing acute diseases and damage increases during planned longterm orbital and interplanetary flights. This requires the use of drugs to correct these maladies. EXPERIMENTAL PARTThe pharmacokinetic investigation involved 10 healthy men (members of the ISS space expeditions) who were divided into two groups of 5 men.The average age in the first group, i.e., those administered the tablet form of acetaminophen, was 44.6 yr (from 39 to 50 yr); in the second group, i.e., those administered encapsulated acetaminophen, 44.4 yr (from 40 to 47 yr).The study procedure and method were approved beforehand by the Commission on Biomedical Ethics of the IMBP RAS. Informed consent was obtained from the volunteers for the space experiment.The pharmacokinetics and bioavailability of the acetaminophen drug forms were studied using its concentration dynamics in saliva because obtaining blood samples under microgravity conditions is difficult and the ability to study acetaminophen pharmacokinetics from its distribution dynamics in saliva had been demonstrated previously [8,9], including during space flights [10].The pharmacokinetics of acetaminophen were studied first approximately two months before the start of the space flight (SF) using the standard protocol.Volunteers were prohibited from taking any drugs, including vi...
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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