Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: https://www.tandfonline.com/loi/iemt20

How do the pharmacokinetics of drugs change in

astronauts in space?

Sara Eyal

To cite this article: Sara Eyal (2020) How do the pharmacokinetics of drugs change in
astronauts in space?, Expert Opinion on Drug Metabolism & Toxicology, 16:5, 353-356, DOI:
10.1080/17425255.2020.1746763

To link to this article: https://doi.org/10.1080/17425255.2020.1746763

Published online: 29 Mar 2020.

Submit your article to this journal

Article views: 3392

View related articles

View Crossmark data

Citing articles: 17 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=iemt20
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY
2020, VOL. 16, NO. 5, 353–356
https://doi.org/10.1080/17425255.2020.1746763
EDITORIAL
How do the pharmacokinetics of drugs change in astronauts in space?
Sara Eyal
Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
ARTICLE HISTORY Received 11 February 2020; Accepted 19 March 2020
KEYWORDS Astronaut; cytochrome P450; International Space Station; microgravity; pharmacokinetics; space travel; spaceflight
1. Introduction
By the beginning of 2020, over 560 individuals have flown in
space, with duration ranging from 15 min to 437 days. Among
these were seven ‘space tourists’, some with known medical
problems, who typically spent over a week onboard the
International Space Station (ISS) [1,2]. As we enter a new era
of commercialized spaceflights, more individuals will be able
to travel to low Earth orbit or even to deep space.
Space travel imposes multiple challenges to the human
body due to microgravity, radiation, confinement, isolation,
changes in circadian rhythm, and stress. The effect depends
on the duration of the mission and its destination and varies
with the phase of the spaceflight. During the first days of
flight, participants may develop space motion sickness. Fluids
shift to the central compartment of the body and the head
with subsequent changes in the concentration of albumin and
other plasma components and in renal metabolism. Within
a few days, fluid redistribution is compensated by diuresis
and loss of plasma and extracellular fluid volume. Longer
stays in space have many physiological consequences, includ-
ing loss of bone mineralization and muscle strength, reduced
cardiovascular capacity, alterations in immune function and in
the microbiome, and neuro-ocular symptoms [1,2]. Those
changes can prompt medication consumption while poten-
tially altering drug handling by the body, as was recently
reviewed in more detail [2]. The present editorial adds recent
examples of the complexities of drug treatment in space,
comparatively summarizes the available pharmacokinetic
parameters in astronauts, and highlights fields of knowledge
and lack thereof.
2. Medication usage in space
Medications have been used during space missions to prevent
or treat conditions associated with spaceflight and for the
management of preexisting illness or ordinary medical com-
plaints. In a recent survey of drug use that was completed by
six crewmembers during flight, there were 20.6 ± 8.4 entries
per subject per flight week [3]. Indications for drug use in
space have included space motion sickness, sleep deficiency,
headache, backache, muscle or joint pain, bone resorption,
congestion, and hypersensitivity reactions [2]. Most recently,
enoxaparin and apixaban were used for treating jugular
CONTACT Sara Eyal sarae@ekmd.huji.ac.il Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
© 2020 Informa UK Limited, trading as Taylor & Francis Group
venous thrombosis in an astronaut onboard the ISS [4]. The
efficacy and safety of these treatments are largely unknown,
and it has been suggested that some medications may be less
effective than expected [5]. However, in addition to pharma-
cokinetics and pharmacodynamics, the nature of disease itself
(e.g. motion sickness and hypercoagulability) might differ in
space.
3. Effects of spaceflight on pharmacokinetics: rigidly
defined areas of doubt and uncertainty
Current knowledge on spaceflight-associated changes in phar-
macokinetics is limited and is based on sporadic evidence. Five
studies evaluated drug pharmacokinetics in crewmembers dur-
ing orbital spaceflight, all relying on the measurement of drug
concentrations in saliva (Table 1). Common to the four studied
compounds (acetaminophen, scopolamine, promethazine, and
antipyrine) is hepatic metabolism as a major route of elimination,
though by different drug-metabolizing enzymes. Several limita-
tions complicate the interpretation of the data from these stu-
dies. First, measuring drug concentrations in saliva could
increase variability and introduce error, given that the saliva:
blood ratios in space are unknown. Second, most studies were
limited by small subject numbers and variation in mission day,
sampling time, route of administration, formulation, food con-
sumption, and lack of data on within-subject variability on the
ground. Third, parameters related to the experimental setting
were only partially described. In the studies conducted by
Lakshmi Putcha’s group, acetaminophen was likely combined
with scopolamine and dexamphetamine (and vice versa), possi-
bly by some crew members but not others, and few pharmaco-
kinetic parameters were reported [6–8]. The paper by
Kovachevich et al. describes a more comprehensive pharmaco-
kinetic analysis but does not indicate the mission day of the
study, which additionally could have varied between participants
[9]. Accordingly, the results of these studies are inconsistent and
often conflicting, with considerable differences between and
within individuals in concentration–time curves and in pharma-
cokinetic parameters. Unfortunately, only one study clearly pre-
sented the volume of distribution and half life data. Despite
those limitations, a theme common to all individuals and studies
was an apparent trend toward altered drug disposition during
spaceflight compared to measurements on Earth.
354 S. EYAL
Table 1. Spaceflight-induced pharmacokinetic changes in humans.
Day of
Drug Dosage form flight
Acetaminophena Tablets (fasting) 2 2
3 2
4 2
Acetaminophen Tablets (fasting)
Capsules (fasting)
Scopolamine Capsules (combined with 0–1
dextroamphetamine) 1–2
2–-3
Promethazine I.M. injection, oral tablet, or rectal 1 9
suppository
Antipyrine Oral (fed state)
*Statistically significant difference.
a
The study was later extended to 12 participants from 7 different flights (with similar results), but the numbers of participants on each study day were not reported
[8].
b
AUC0-∞.
c
Inferred from reported reduction in oral clearance.
Given the difficulties of studies in astronauts, terrestrial
human bedrest and rodent analog models have been used
to simulate the effects of spaceflight on drug disposition.
While these models can mimic microgravity-induced fluid
shifts, they do not account for many of the other features of
spaceflight [5]. Several studies compared the liver size and
expression or activity of drug-metabolizing enzymes between
rodents flown to space and ground controls. The majority of
these studies demonstrated smaller microsomal protein or
cytochrome P450 content and reduced activity of glutathione
S-transferase (GST). Significantly lower GST activity can predis-
pose cells to oxidative damage and affect the metabolism of
leukotrienes, prostaglandins, and medications. This can lead to
accumulation of drugs or their metabolites, including N-acetyl-
p-benzoquinone imine (NAPQI), the hepatotoxic metabolite of
acetaminophen [12].
Changes in the expression of individual CYP450 enzymes
were not consistent. For instance, the effect of spaceflight on
murine Cyp2d26 expression ranged from no change to
a statistically significant, 1.5-fold increase [2]. Limitations of
the experiments in animal models resemble those of studies
which involved astronauts but additionally include differences
in species and maintenance conditions as well as delays in
post-flight recovery of the animals. Yet the alterations in the
expression of drug-metabolizing enzymes imply that drug
elimination, prodrug activation, or formation of toxic metabo-
lites can all differ in space.
Compared to macro ADME parameters, even less is known
about processes that affect the cellular kinetics of drugs.
Microgravity-induced alterations in membrane fluidity can
affect drug diffusion across membranes and the activity of
uptake and efflux transporters. The only drug transporter
whose functional activity in microgravity was reported is
MRP2, which was shown to be less active during a parabolic
flight [2]. However, spaceflight can induce changes in trans-
porter expression. The protein levels of the solute carrier
organic anion transporter family, member 1b2 (Slco1b2),
were 1.7-fold higher in livers from mice which were flown on
a biosatellite for 30 days than in re-adapted mice. In micro-
organisms, ABC transporter genes were upregulated [13,14] in
space, and expression of P-glycoprotein (P-gp) increased
2.3-fold in slowly-growing human fibroblasts [15]. Such
Number of Volume of Half-
participant Cmax Tmax AUC distribution life Reference
↑ ↓ [7]
↑ ↑
↓ ↑ ↓?
5 ↓ ↑ ↑ ↓ ↑ [9]
5 ↓ ↓* ↑b ↑* ↑*
2 ↓ ↑ [6]
1 ↑ ↔
1 ↑ ↓
↓ ↑ ↓ ↑ [10]
2 ↓↑ c
[11]
changes in P-gp function could impact the efficacy or toxicity
of the above-mentioned apixaban.
Modified pharmacokinetics in microgravity may result from
both physical and physiological factors. The former were sug-
gested to play a significant role in drug absorption, e.g., by
altering the distribution of aerosols within the airways and the
more random positioning of oral dosage forms within the
stomach (instead of floating or sinking) [2]. Physiological fac-
tors that can directly affect absorption include delayed gastric
emptying due to space motion sickness (and medications
taken to treat it) and altered gut microbiome [2,5]. Altered
blood flow to tissues can translate to changes in each of the
ADME parameters. Dehydration and fluctuations in serum
albumin levels can affect drug volume of distribution and
excretion. Moreover, shifts in global and local cerebral fluid
distribution and blood flow may affect drug distribution
within brain tissue thus potentially modulating drug efficacy
or cerebral adverse effect (e.g. those related to the cerebel-
lum) [2,4]. An additional space-related factor that should be
taken into account is altered immune function that was pre-
viously shown to contribute to pharmacokinetic variability [2].
In the absence of clear evidence, many fundamental phar-
macokinetic assumptions need to be questioned. For instance,
we do not know whether only unbound drug distributes to
tissues, if flow-limited elimination of drugs becomes intrinsic
clearance-limited or vice versa, and whether transporter-based
processes are equally important in space. These challenges,
together with the paucity of essential pharmacodynamic data,
make astronauts an ‘orphan’ population with respect to drug
efficacy and safety.
4. Pharmacogenetics in astronauts and space
travelers
Preemptive pharmacogenetic typing of astronauts, e.g. for
selected CYP isoforms and drug transporters, has been sug-
gested as means for supporting individualization of pharma-
cological treatment [16]. However, no findings from such
studies are currently available. The contribution of genetics
by itself to pharmacokinetic variability in space is unknown.
Environmental factors might be pronounced especially during
the first days after launch (as was reported for acetaminophen

[8]) and initially after return to Earth, which may also encom-
pass the entire duration of touristic flights. For longer stays in
space, the ISS offers more uniform environment in terms of
nutrition, temperature, and fitness. Notably, the ISS has hosted
astronauts of many nations, including the United States,
Russia, China, India, Japan, Brazil, Israel, and the United Arab
Emirates. Current pharmacogenetic data which guide treat-
ment in some ethnic populations do not apply to others,
and can even lead to under- or overestimation of the dose.
Astronauts additionally vary in gender and age. The youngest
astronaut, Gherman Titov, was 25 years when he was launched
as the second human in orbit, and John Glen was 77 years old
when he flew aboard the Space Shuttle for his second mission
[17]. Current astronauts are not that young or that old, but the
age of space tourists and their medical background are likely
to be variable. This does not rule out the importance of
gaining pharmacogenetic data and connecting it to outcomes
in future studies in space.
5. Expert opinion
Despite decades of drug use by astronauts during space missions,
data on drug disposition under microgravity conditions are scarce
and inconsistent. The few available reports suggest that space-
flight might affect drug absorption, distribution, and elimination,
with high between- and within-subject variability. No major
adverse drug effects on astronauts in space have been reported
so far. Yet associations between drug use and changes in perfor-
mance of crewmembers cannot be ruled out and might be
detected in future analyses. Moreover, with expansion of space-
flight to deep space, larger exposure to galactic cosmic radiation
may become an additional variable with yet unknown effects on
human physiology that could increase drug use while altering their
disposition. Despite those risks, randomized, controlled pharma-
cokinetic studies in astronauts in space do not seem to be prior-
itized. For instance, a search for the terms astronaut and
microgravity in ClinicalTrials.gov (March 2020) yielded 35 and 34
entries, respectively, of which one related to drug efficacy. NASA’s
Human Research Roadmap [18] does not include pharmacoki-
netics-related studies other than a completed but yet unpublished
analysis of hepatic drug-metabolizing enzymes in mice. In the
absence of new pharmacokinetic studies in astronauts, publication
of the missing raw data and derived pharmacokinetic parameters
of older studies (e.g. changes in oral clearance) is desirable. The
accumulating ‘real-world’ data on drug use and effectiveness
onboard the ISS can provide a basis for artificial intelligence-
based tool for treatment personalization. In addition, outliers
within the astronaut population can provide valuable data on
factors that contribute to pharmacokinetic and pharmacodynamic
variability.
Ideally, pharmacokinetics in astronauts would become more
predictable with increased mechanistic understanding of the phy-
siological changes that occur during spaceflight and upon return
to Earth. An important tool for such studies are microphysiological
(organ-on-a-chip) systems that have already been flown to space
[19]. Although such systems do not capture complexities of the
entire organism, they can provide important data for in vitro-to-in
vivo extrapolations. Unmanned, remote-controlled minilabs are
EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY 355
emerging as means for conducting such studies without the
need of astronaut intervention. Such platforms can be launched
to the ISS or be operated onboard satellites or unmanned shuttles
[20]. Eventually, lessons gained from these studies might apply to
Earth as well, as was previously demonstrated for other space-
based knowledge and technologies.
Rare opportunities for serial blood sampling from astro-
nauts, e.g. NASA’s Twin Study or the case of anticoagulant
treatment onboard the ISS, should be utilized for measuring
drug concentrations. Drugs are commonly used by astronauts,
and pharmacokinetic studies are important for dosage adjust-
ment. The recent incident of anticoagulant use onboard the
ISS reminds us that medical emergencies can occur in space,
and that the medical team’s base of knowledge for decision-
making should be as broad as possible.
Funding
This paper was not funded.
Declaration of Interest
S Eyal is on a sabbatical leave at SpacePharma, Israel, from 1 July 2019.
The author has no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript except
for those disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Sara Eyal http://orcid.org/0000-0003-1275-6094
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Stepanek J, Blue RS, Parazynski S. Space medicine in the era of
civilian spaceflight. N Engl J Med. 2019;380(11):1053–1060.
•• Discusses medical aspects of space flight.
2. Eyal S, Derendorf H. Medications in space: in search of
a pharmacologist’s guide to the galaxy. Pharm Res. 2019;36
(10):148.
•• Presents current knowledge on physiological changes and
pharmacokinetics in space.
3. Wotring VE, Smith LK. Dose tracker application for collecting med-
ication use data from international space station crew. Aerosp Med
Hum Perform. 2020 Jan 1;91(1):41–45.
•• Describes current NASA's efforts to obtain information on drug
usage in space.
4. Aunon-Chancellor SM, Pattarini JM, Moll S, et al. Venous thrombo-
sis during spaceflight. N Engl J Med. 2020 Jan 2;382(1):89–90.
• A case report of thromboembolism in space.
5. Blue RS, Bayuse TM, Daniels VR, et al. Supplying a pharmacy for
NASA exploration spaceflight: challenges and current
understanding. NPJ Microgravity. 2019;5(1):14.
•• Reviews issues associated with drug treatment in astronauts.
6. Cintron NM, Putcha L, Chen Y-M, et al. Inflight salivary pharmaco-
kinetics of scopolamine and dextroamphetamine. In: Bungo MW,
Bagian TM, Bowman MA, et al., editors. NASA technical
356 S. EYAL
memorandum 58280. Results of the life sciences DSOs conducted
aboard the space shuttle 1981-1986. Huston, TX: National
Aeronautics and Space Administration; 1987. p. 25–29.
•• Among the earliest published pharmacokinetic studies in
space.
7. Cintron NM, Putcha L, Vanderploeg JM, et al. Inflight pharmacoki-
netics of acetaminophen in saliva. In: Bungo MW, Bagian TM,
Bowman MAeditors. NASA technical memorandum 58280. Results
of the life sciences DSOs conducted aboard the space shuttle 1981-
1986. Huston, TX: National Aeronautics and Space Administration;
1987. p. 19–23.
•• Among the earliest published pharmacokinetic studies in
space.
8. Putcha L, Cintron NM. Pharmacokinetic consequences of
spaceflight. Ann N Y Acad Sci. 1991 Feb 28;618:615–618.
9. Kovachevich IV, Kondratenko SN, Starodubtsev AK, et al.
Pharmacokinetics of acetaminophen administered in tablets and
in capsules under long term space flight conditions. Pharm Chem J.
2009;43(3):130–133.
•• Presents the most detailed published pharmacokinetic analy-
sis of data collected in astronauts in space. Provides insights
on factors associated with altered drug absorption in
microgravity.
10. Boyd J, Wang Z, Putcha L Bioavailability of promethazine during
spaceflight. Tech. Rep. NASA/TM-2009-01322, NASA Johnson Space
Center. [updated 2009 Jan 01; cited 2020 Feb 7]. Available from:
https://ntrs.nasa.gov/search.jsp?R=20090001322.
11. Putcha L, Kovachevich I Physiologic alterations and pharmacoki-
netic changes during space flight (2.3.1). [cited 2020 Feb 7].
Available from: https://lsda.jsc.nasa.gov/Experiment/exper/359.
12. Frank J, Gonzalez FJ, Coughtrie M, et al. Drug Metabolism. In:
Brunton LL, Hilal-Dandan R, Knollmann BC, editors. Goodman &
Gilman’s: the pharmacological basis of therapeutics. New York:
McGraw-Hill Medical; 2018. p. 13e.
13. Crabbé A, Nielsen-Preiss SM, Woolley CM, et al. Spaceflight
enhances cell aggregation and random budding in Candida
albicans. PloS One. 2013;8(12):e80677.
14. Morrison MD, Fajardo-Cavazos P, Nicholson WL. Comparison of
Bacillus subtilis transcriptome profiles from two separate mis-
sions to the International Space Station. NPJ Microgravity. 2019
Jan 07;5(1):1.
15. Zhang Y, Lu T, Wong M, et al. Transient gene and microRNA
expression profile changes of confluent human fibroblast cells in
spaceflight. Faseb J. 2016 Jun;30(6):2211–2224.
16. Stingl JC, Welker S, Hartmann G, et al. Where failure is not an
option -personalized medicine in astronauts. PloS One. 2015;10
(10):e0140764.
• An analysis of potential sources for pharmacogenetic variabil-
ity with regard to drugs available onbord the ISS.
17. European Space Agency. Frequently asked questions – ESA astro-
nauts. [cited 2020 Feb 1]. Available from: https://www.esa.int/
Science_Exploration/Human_and_Robotic_Exploration/Astronauts/
Frequently_asked_questions_ESA_astronauts
18. National Aeronautics and Space Administration. Pharm03: we do
not know the extent to which spaceflight alters pharmacokinetics.
[updated 2019 Jul 31; cited 2020 Mar 16]. Available from: https://
humanresearchroadmap.nasa.gov/Gaps/gap.aspx?i=542
19. Low LA, Giulianotti MA. Tissue chips in space: modeling human
diseases in microgravity. Pharm Res. 2019;37(1):8.
• Presents the Tissues in Space program.
20. Amselem S. Remote controlled autonomous microgravity lab plat-
forms for drug research in space. Pharm Res. 2019;36(12):183.
• An account of platforms for studies in simulated and real
microgravity.