Pharmacogenomics in Spaceflight

  • Michael A. SchmidtEmail author
  • Caleb M. Schmidt
  • Thomas J. Goodwin
Living reference work entry


Pharmacogenomics is the study of how genes influence an individual’s response to medication. By extension, pharmacogenomics is the precise analysis of gene variants that influence the regulation of drug metabolism and the attendant development of therapeutic strategies. Whereas traditional pharmacokinetics and pharmacodynamics are applied to populations in order to understand the range of a drug’s effects, pharmacogenomics can be used to personalize drug therapy to an individual. In short, pharmacogenomics represents an emergent method available to tailor drug therapy to the individual astronaut, so that the drug countermeasure solution optimizes the chance for benefit (efficacy), while minimizing the chance for adverse events (safety). While the application of pharmacogenomics is progressing on Earth, there is presently almost no application of pharmacogenomics in space. This represents a substantial gap in our capability, but it also represents an opportunity to better enable humans to thrive in the space environment. The present review explores the fundamentals of pharmacogenomics, which includes examination of the genetic variants of the primary drug-metabolizing enzymes. It next briefly summarizes the limited evidence for how the space condition may influence these systems. The pharmacogenomic implications of the current ISS drug list are explored by example. A hypothetical design reference mission is proposed to illustrate how pharmacogenomics might be employed in the space environment. In general, we highlight how the application of intelligent clinical pharmacogenomics to astronauts can be used to guide the use of pharmaceuticals in space today, while the much-needed prospective pharmacogenomic research is conducted in parallel.


Pharmacogenomics Pharmacometabolomics Personalized medicine Precision medicine Spaceflight Astronaut CYP450 Drug metabolism 


  1. Alessandrini M, Chaudhry M, Dodgen TM et al (2016) Pharmacogenomics and global precision medicine in the context of adverse drug reactions: top 10 opportunities and challenges for the next decade. OMICS 20(10):593–603PubMedPubMedCentralCrossRefGoogle Scholar
  2. Anselm V, Novikova S, Zgoda V (2017) Re-adaption on earth after spaceflights affects the mouse liver proteome. Int J Mol Sci 18:1763PubMedCentralCrossRefGoogle Scholar
  3. Antonsen E, Bayuse T, Blue R et al (2017) NASA evidence report: Risk of adverse health outcomes and decrements in performance due to in-flight medical conditions. (accessed March 20, 2018)
  4. Baba T, Nishimura M, Kuwahara Y et al (2008) Analysis of gene and protein expression of cytochrome P450 and stress-associated molecules in rat liver after spaceflight. Pathol Int 58(9):589–595PubMedCrossRefGoogle Scholar
  5. Bahar MA, Setiawan D, Hak E et al (2017) Pharmacogenetics of drug-drug interaction and drug-drug-gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6. Pharmacogenomics 8:701–739CrossRefGoogle Scholar
  6. Beger RD, Dunn W, Schmidt MA et al (2016) Metabolomics enables precision medicine: “A white paper, community perspective”. Metabolomics 12(9):149PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bièche I, Narjoz C, Asselah T, Vacher S, Marcellin P, Lidereau R, Beaune P, de Waziers I (2007) Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet Genomics. 17(9):731–42PubMedCrossRefGoogle Scholar
  8. Casero D, Gill K, Sridharan V et al (2017) Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome. Microbiome 5:105PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chu T (2014) Gender differences in pharmacokinetics. US Pharm 39(9):40–43Google Scholar
  10. Chung HC, Kim SH, Lee MG et al (2001) Mitochondrial dysfunction by gamma-irradiation accompanies the induction of cytochrome P450 2E1 (CYP2E1) in rat liver. Toxicology 161(1–2):79–91PubMedCrossRefGoogle Scholar
  11. Clayton TA, Baker D, Lindon JC et al (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci 106:14728–14733PubMedCrossRefGoogle Scholar
  12. Crettol S, Petrovic N, Murray M (2010) Pharmacogenetics of phase I and phase II drug metabolism. Curr Pharm Des 16(2):204–219PubMedCrossRefGoogle Scholar
  13. Dean L (2012) Codeine Therapy and CYP2D6 Genotype. Sep 20 2012 [Updated 2017 Mar 16]. In: Pratt V, McLeod H, Dean L, et al. (eds) Medical Genetics Summaries [Internet]. National Center for Biotechnology Information (US), BethesdaGoogle Scholar
  14. Desta Z, Flockhart DA (2017) Pharmacogenetics of Drug Metabolism. In: David Robertson D, Williams GH (eds) Clinical and Translational Science: Principles of Human Research, 2nd edn. Elsevier, Amsterdam, pp 327–345CrossRefGoogle Scholar
  15. Du B, Daniels VR, Vaksman Z et al (2011) Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS Journal 13(2):299–308PubMedCrossRefGoogle Scholar
  16. Flockhart DA (2007) Drug interactions: cytochrome P450 drug interaction table. Indiana University School of Medicine. Accessed Apr 2018
  17. Franklin MR (2007) Phase II biotransformation reaction – Glutathione-S-Transferase. In: Enna SJ, Bylund DB (eds) xPharm: the comprehensive pharmacology reference. Elsevier, Amsterdam, pp 1–8Google Scholar
  18. Gaedigk A, Simon SD, Pearce RE et al (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83:234–242PubMedCrossRefGoogle Scholar
  19. Gaedigk A, Dinh JC, Jeong H et al (2018) Ten years’ experience with the CYP2D6 activity score: a perspective on future investigations to improve clinical predictions for precision therapeutics. J Pers Med 8(2):pii:E15. Scholar
  20. Gasche Y, Daali Y, Fathi M et al (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351:2827–2831PubMedCrossRefGoogle Scholar
  21. Ghodke-Puranik YA, Lamba JK (2017) Pharmacogenomics. In: Patwardhan B, Rathnam Chaguturu R (eds) Innovative approaches in drug discovery: ethnopharmacology, systems biology and holistic targeting, 1st edn. Academic, Cambridge, MA, pp 195–234CrossRefGoogle Scholar
  22. Haiser HJ, Turnbaugh PJ (2013) Developing a metagenomic view of xenobiotic metabolism. Pharmacol Res 69:21–31PubMedCrossRefGoogle Scholar
  23. Hitchen L (2006) Adverse drug reactions result in 250,000 UK admissions a year. Br Med J 332:1109Google Scholar
  24. Hodges, RE, Minich, DM (2015) Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application, Journal of Nutrition and Metabolism. 2015, Article ID 760689, 23Google Scholar
  25. Hu S, Kim MH, McClellan GE et al (2009) Modeling the acute health effects of astronauts from exposure to large solar particle events. Health Phys 96:465–476PubMedCrossRefGoogle Scholar
  26. Huang R, Southall N, Wang Y et al (2011) The NCGC Pharmaceutical Collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci Transl Med 3:80ps16PubMedPubMedCentralCrossRefGoogle Scholar
  27. Inano H, Ishii-Ohba H, Suzuki K et al (1990) Reasons for reduced activities of 17 alpha-hydroxylase and C17-C20 lyase in spite of increased contents of cytochrome P-450 in mature rat testis fetally-irradiated with 60Co. J Steroid Biochem 35(6):711–714PubMedCrossRefGoogle Scholar
  28. Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89:31–41PubMedCrossRefGoogle Scholar
  29. Jain K (2009) Textbook of personalized medicine. Springer, New YorkCrossRefGoogle Scholar
  30. James MO, Ambadapadi S (2013) Interactions of cytosolic sulfotransferases with xenobiotics. Drug Metab Rev 45(4):401–414PubMedCrossRefGoogle Scholar
  31. Josephy PD (2010) Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology. Human Genomic Proteomic 2010:876940Google Scholar
  32. Kaddurah-Daouk R, Weinshilboum RM, Pharmacometabolomics Research Network (2014) Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clin Pharmacol Ther 95(2):154–167PubMedCrossRefGoogle Scholar
  33. Kanai M, Tong W, Sugihara E et al (2003) Involvement of poly(ADP-Ribose) polymerase 1 and poly(ADP-Ribosyl)ation in regulation of centrosome function. Mol Cell Biol 23:2451–2462PubMedPubMedCentralCrossRefGoogle Scholar
  34. Kim M, Mauro S, Gevry N et al (2004) NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. Cell 119:803–814PubMedCrossRefGoogle Scholar
  35. Kirkland J (2012) Niacin requirements for genomic stability. Mutat Res 733:14–20PubMedCrossRefGoogle Scholar
  36. Kirwan, JA, Brennan, L, Broadhurst, D, Fiehn, O, Cascante, M, Dunn, W, Schmidt, MA, Velagapudi, V (2018) Preanalytical processing and biobanking procedures of biological samples for metabolomics research: a white paper, community perspective. (for “Precision Medicine and Pharmacometabolomics Task Group” - The Metabolomics Society Initiative). Clinical Chemistry 64:8.PubMedCrossRefGoogle Scholar
  37. Knights KM, Sykes MJ, Miners JO (2007) Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids. Expert Opin Drug Metab Toxicol 3(2):159–168PubMedCrossRefGoogle Scholar
  38. Lam V, Moulder JE, Salzman NH et al (2012) Intestinal microbiota as novel biomarkers of prior radiation exposure. Radiat Res 177:573–583. Scholar
  39. Lee SJ, Goldstein JA (2005) Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics 6(4):357–371PubMedCrossRefGoogle Scholar
  40. Liska DJ (1998) The detoxification enzyme system. Altern Med Rev 3(3):187–198PubMedGoogle Scholar
  41. Mallhi TH, Sarriff A, Adnan AS et al (2015) Effect of fruit/vegetable-drug interactions on CYP450, OATP and p-Glycoprotein: a systematic review. Trop J Pharm Res 14(10):1927–1935CrossRefGoogle Scholar
  42. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR (2018) Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun 9(1):1286PubMedPubMedCentralCrossRefGoogle Scholar
  43. Merrill AHJ, Hoel M, Wang E et al (1990) Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887. FASEB J 4(1):95–100PubMedCrossRefGoogle Scholar
  44. Meunier B, de Visser SP, Shaik S (2004) Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes. Chem Rev 104(9):3947–3980PubMedCrossRefGoogle Scholar
  45. Moskaleva N, Moysa A, Novikova S et al (2015) Spaceflight effects on cytochrome P450 content in mouse liver. PLoS One 10(11):e0142374. Scholar
  46. National Aeronautics and Space Administration (NASA) (2016) Emergency medical procedures manual for the International Space Station (ISS) partial. FOIA Case Number 16-JSC-F-00174Google Scholar
  47. Packey CD, Ciorba MA (2010) Microbial influences on the small intestinal response to radiation injury. Curr Opin Gastroenterol 26:88–94. Scholar
  48. Rabot S, Szylit O, Nugon-Baudon L et al (2000) Variations in digestive physiology of rats after short duration flights aboard the US space shuttle. Dig Dis Sci 45(9):1687–1695PubMedCrossRefGoogle Scholar
  49. Rendic S, Guengerich FP (2012) Summary of information on the effects of ionizing and non-ionizing radiation on cytochrome P450 and other drug metabolizing enzymes and transporters. Curr Drug Metab 13(6):787–814PubMedPubMedCentralCrossRefGoogle Scholar
  50. Schmidt MA, Goodwin TJ (2013) Personalized medicine in human space flight: using omics based analyses to develop individualized countermeasures that enhance astronaut safety and performance. Metabolomics 9:1134–1156PubMedPubMedCentralCrossRefGoogle Scholar
  51. Schmidt MA, Goodwin TJ, Pelligra R (2016) Incorporation of omics analyses into artificial gravity research for space exploration countermeasure development. Metabolomics 12:36PubMedPubMedCentralCrossRefGoogle Scholar
  52. Shah RR, Gaedigk A (2018) Precision medicine: does ethnicity information complement genotype-based prescribing decisions? Ther Adv Drug Saf 9(1):45–62PubMedCrossRefGoogle Scholar
  53. Shahrokh K, Cheatham TE, Yost GS (2012) Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen. Biochim Biophys Acta 1820(10):1605–1617PubMedPubMedCentralCrossRefGoogle Scholar
  54. Sim E, Abuhammad A, Ryan A (2014) Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br J Pharmacol 171(11):2705–2725PubMedPubMedCentralCrossRefGoogle Scholar
  55. Sissi C, Palumbo M (2009) Effects of magnesium and related divalent metal ions in topoisomerase structure and function. Nucleic Acids Res 37(3):702–711PubMedPubMedCentralCrossRefGoogle Scholar
  56. Spector AA, Kim HY (2015) Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism. Biochim Biophys Acta 1851(4):356–365PubMedCrossRefGoogle Scholar
  57. Stingl JC, Welker S, Hartmann G et al (2015) Where failure is not an option – personalized medicine in astronauts. PLoS One 10(10):e0140764PubMedPubMedCentralCrossRefGoogle Scholar
  58. Van Booven D, Marsh S, McLeod H et al (2010) Cytochrome P450 2C9-CYP2C9. Pharmacogenet Genomics 20(4):277–281PubMedPubMedCentralGoogle Scholar
  59. Wang B, Yang LP, Zhang XZ et al (2009) New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme. Drug Metab Rev 41(4):573–643PubMedCrossRefGoogle Scholar
  60. Wu A (2011) Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteomics 8:12PubMedPubMedCentralCrossRefGoogle Scholar
  61. Yip LY, Chan EC (2015) Investigation of host-gut microbiota modulation of therapeutic outcome. Drug Metab Dispos 43(10):1619–1631PubMedCrossRefGoogle Scholar
  62. Zanger UM, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 138(1):103–141PubMedCrossRefGoogle Scholar
  63. Zeitlin C (2012) Physical interactions of charged particles for radiotherapy and space applications. Health Phys 103:540–546PubMedCrossRefGoogle Scholar
  64. Zeitlin C, Hassler DM, Cucinotta FA et al (2013) Measurements of energetic particle radiation in transit to mars on the mars science laboratory. Science 340(6136):1080–1084PubMedCrossRefGoogle Scholar
  65. Zhang Y, Klein K, Sugathan A et al (2011) Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One 6:e23506PubMedPubMedCentralCrossRefGoogle Scholar
  66. Zhang M, An C, Gao Y et al (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47PubMedCrossRefGoogle Scholar
  67. Zhou SF, Zhou ZW, Huang M (2010) Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology 278:165–188PubMedCrossRefGoogle Scholar


  1. Clinical Pharmacogenetics Implementation Consortium (CPIC) (
  2. Human Cytochrome P450 (CYP) Allele Nomenclature Database ( Pharmacogene Variation Consortium (PharmVar;
  3. Pharmacogenomics Knowledgebase (PharmGKB) website (

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Michael A. Schmidt
    • 1
    • 2
    Email author
  • Caleb M. Schmidt
    • 2
  • Thomas J. Goodwin
    • 1
    • 2
  1. 1.Advanced Pattern Analysis & Countermeasures GroupBoulderUSA
  2. 2.Sovaris Aerospace, LLCBoulderUSA

Section editors and affiliations

  • Marlise Araújo dos Santos
    • 1
  1. 1.Porto AlegreBrazil

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