Archives of Pharmacal Research

, Volume 38, Issue 11, pp 2076–2082 | Cite as

Pharmacokinetics of enzalutamide, an anti-prostate cancer drug, in rats

  • Tae-Heon Kim
  • Jong-Woo Jeong
  • Ji-Hye Song
  • Kyeong-Ryoon Lee
  • Sunjoo Ahn
  • Sung-Hoon Ahn
  • Sungsub KimEmail author
  • Tae-Sung KooEmail author
Research Article


We characterized the pharmacokinetics of enzalutamide, a novel anti-prostate cancer drug, in rats after intravenous and oral administration in the dose range 0.5–5 mg/kg. Tissue distribution, liver microsomal stability, and plasma protein binding were also examined. After intravenous injection, systemic clearance, volumes of distribution at steady state (Vss), and half-life (T½) remained unaltered as a function of dose, with values in the ranges of 80.4–86.3 mL/h/kg, 1020–1250 mL/kg, and 9.13–10.6 h, respectively. Following oral administration, absolute oral bioavailability was 89.7 % and not dose-dependent. The recoveries of enzalutamide in urine and feces were 0.0620 and 2.04 %, respectively. Enzalutamide was distributed primarily in 10 tissues (brain, liver, kidneys, testis, heart, spleen, lungs, gut, muscle, and adipose) and tissue-to-plasma ratios of enzalutamide ranged from 0.406 (brain) to 10.2 (adipose tissue). Further, enzalutamide was stable in rat liver microsomes, and its plasma protein binding was 94.7 %. In conclusion, enzalutamide showed dose-independent pharmacokinetics at intravenous and oral doses of 0.5–5 mg/kg. Enzalutamide distributed primarily to 10 tissues and appeared to be eliminated primarily by metabolism.


Enzalutamide Pharmacokinetics Tissue distribution Metabolsim Excretion 



This work was supported by the research fund of Chungnam National University.


  1. Astellas. 2012. Full prescribing information.
  2. Crawford, E.D., M.A. Eisenberger, D.G. McLeod, J.T. Spaulding, R. Benson, F.A. Dorr, B.A. Blumenstein, M.A. Davis, and P.J. Goodman. 1989. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. The New England Journal of Medicine 321: 419–424.CrossRefPubMedGoogle Scholar
  3. Davies, B., and T. Morris. 1993. Physiological parameters in laboratory animals and humans. Pharmaceutical Research 10: 1093–1095.CrossRefPubMedGoogle Scholar
  4. El-Amm, J., N. Patel, A. Freeman, and J.B. Aragon-Ching. 2013. Metastatic castration-resistant prostate cancer: critical review of enzalutamide. Clinical Medicine Insights: Oncology 7: 235–245.PubMedCentralPubMedGoogle Scholar
  5. FDA U. 2001. Guidance for industry, bioanalytical methods validation.
  6. Houston, J.B., and D.J. Carlile. 1997. Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metabolism Reviews 29: 891–922.CrossRefPubMedGoogle Scholar
  7. Huggins C, Hodges CV. (2002). Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. The Journal of Urology 167:948–51; discussion 52.Google Scholar
  8. Kahl, P., L. Gullotti, L.C. Heukamp, S. Wolf, N. Friedrichs, R. Vorreuther, G. Solleder, P.J. Bastian, J. Ellinger, E. Metzger, et al. 2006. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Research 66: 11341–11347.CrossRefPubMedGoogle Scholar
  9. Koo, T.S., S.J. Kim, D.J. Ha, M. Baek, and H. Moon. 2011. Pharmacokinetics, brain distribution, and plasma protein binding of the antiepileptic drug lacosamide in rats. Archives of Pharmacal Research 34: 2059–2064.CrossRefPubMedGoogle Scholar
  10. Lee, K.R., Y.J. Chae, and T.S. Koo. 2011. Pharmacokinetics of lurasidone, a novel atypical anti-psychotic drug, in rats. Xenobiotica; The Fate of Foreign Compounds in Biological Systems 41: 1100–1107.CrossRefPubMedGoogle Scholar
  11. Metzger, E., M. Wissmann, N. Yin, J.M. Muller, R. Schneider, A.H. Peters, T. Gunther, R. Buettner, and R. Schule. 2005. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437: 436–439.PubMedGoogle Scholar
  12. Mullard, A. 2013. 2012 FDA drug approvals. Nature Reviews Drug Discovery 12: 87–90.CrossRefPubMedGoogle Scholar
  13. Nguyen, T.V., M. Yao, and C.J. Pike. 2007. Flutamide and cyproterone acetate exert agonist effects: induction of androgen receptor-dependent neuroprotection. Endocrinology 148: 2936–2943.CrossRefPubMedGoogle Scholar
  14. Pang, K.S., and M. Rowland. 1977. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. Journal of Pharmacokinetics and Biopharmaceutics 5: 625–653.CrossRefPubMedGoogle Scholar
  15. Parkin, D.M., F. Bray, J. Ferlay, and P. Pisani. 2005. Global cancer statistics, 2002. CA: A Cancer Journal for Clinicians 55: 74–108.Google Scholar
  16. Peters, S.A. 2012. Physiologically-based pharmacokinetic (PBPK) modeling and simulations: principles, methods, and applications in the pharmaceutical industry. Hoboken: Wiley.CrossRefGoogle Scholar
  17. Scher, H.I., T.M. Beer, C.S. Higano, A. Anand, M.E. Taplin, E. Efstathiou, D. Rathkopf, J. Shelkey, E.Y. Yu, J. Alumkal, et al. 2010. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 375: 1437–1446.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Scher, H.I., K. Fizazi, F. Saad, M.E. Taplin, C.N. Sternberg, K. Miller, R. de Wit, P. Mulders, K.N. Chi, N.D. Shore, et al. 2012. Increased survival with enzalutamide in prostate cancer after chemotherapy. New England Journal of Medicine 367: 1187–1197.CrossRefPubMedGoogle Scholar
  19. Semenas, J., N. Dizeyi, and J.L. Persson. 2013. Enzalutamide as a second generation antiandrogen for treatment of advanced prostate cancer. Drug Design Development and Therapy 7: 875–881.Google Scholar
  20. Song, J.H., T.H. Kim, J.W. Jung, N. Kim, S.H. Ahn, S.O. Hwang, N.S. Kang, S.E. Yoo, and T.S. Koo. 2014. Quantitative determination of enzalutamide, an anti-prostate cancer drug, in rat plasma using liquid chromatography-tandem mass spectrometry, and its application to a pharmacokinetic study. Biomedical Chromatography 28(8): 1112–1117.CrossRefPubMedGoogle Scholar
  21. Tran, C., S. Ouk, N.J. Clegg, Y. Chen, P.A. Watson, V. Arora, J. Wongvipat, P.M. Smith-Jones, D. Yoo, A. Kwon, et al. 2009. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324: 787–790.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2015

Authors and Affiliations

  • Tae-Heon Kim
    • 1
  • Jong-Woo Jeong
    • 1
  • Ji-Hye Song
    • 1
  • Kyeong-Ryoon Lee
    • 2
  • Sunjoo Ahn
    • 3
    • 4
  • Sung-Hoon Ahn
    • 3
    • 5
  • Sungsub Kim
    • 1
    Email author
  • Tae-Sung Koo
    • 1
    Email author
  1. 1.Graduate School of New Drug Discovery and DevelopmentChungnam National UniversityDaejeonKorea
  2. 2.Life Science Research InstituteDaewoong Pharmaceutical CorporationYonginKorea
  3. 3.Center for Drug Discovery TechnologyKorea Research Institute of Chemical TechnologyDaejeonKorea
  4. 4.Department of Medicinal Chemistry & PharmacologyKorea University of Science and TechnologyDaejeonKorea
  5. 5.College of PharmacyKangwon National UniversityChuncheonKorea

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