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Absorption, Distribution, Metabolism, and Excretion of the Androgen Receptor Inhibitor Enzalutamide in Rats and Dogs

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Abstract

Background and Objectives

Enzalutamide is an androgen receptor inhibitor that has been approved in several countries. Absorption, distribution, metabolism, and excretion (ADME) data in animals would facilitate understanding of the efficacy and safety profiles of enzalutamide, but little information has been reported in public. The purpose of this study was to clarify the missing ADME profile in animals.

Methods

ADME of 14C-enzalutamide after oral administration as Labrasol solution were investigated in non-fasted male Sprague–Dawley rats and beagle dogs.

Results

Plasma concentrations of 14C-enzalutamide peaked in rats and dogs at 6–8 h after a single oral administration. In most tissues, radioactivity concentration peaked at 4 h after administration. Excluding the gastrointestinal tract, tissues with the highest concentration of radioactivity were liver, fat, and adrenal glands. The tissue concentrations of radioactivity declined below the limit of quantitation or <0.89 % of maximum concentration by 168 h post-dose. Two known metabolites (M1 and M2) and at least 15 novel possible metabolites were detected in this study. M1 was the most abundant metabolite in both rats and dogs. Unchanged drug was a minor component in excreta. In intact rats, the mean urinary and fecal excretion of radioactivity accounted for 44.20 and 49.80 % of administered radioactivity, respectively. In intact dogs, mean urinary and fecal excretion was 62.00 and 22.30 % of the administered radioactivity, respectively.

Conclusions

Rapid oral absorption was observed in rats and dogs when 14C-enzalutamide was administered as Labrasol solution. Tissue distribution in rats was clarified. The elimination of enzalutamide is mediated primarily by metabolism. Species differences were observed in excretion route.

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Notes

  1. XTANDI is a registered trademark of Astellas Pharma Inc.

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Acknowledgments

We thank R. Ng of Medivation for providing enzalutamide and its metabolites, and Q. Li of Astellas Pharma and J. Mordenti of Medivation for their helpful advice.

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Authors and Affiliations

  1. Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan

    Yoshiaki Ohtsu, Katsuhiro Suzuki & Hiroshi Arai

  2. Clinical Pharmacology and DMPK, Medivation, Inc., 525 Market Street, 36th Floor, San Francisco, CA, 94105, USA

    Jacqueline A. Gibbons

  3. Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI, 53704, USA

    Michael E. Fitzsimmons

  4. Sekisui Medical Co., Ltd., 2117 Muramatsu, Tokai, Naka, Ibaraki, 319-1182, Japan

    Kohei Nozawa

Authors
  1. Yoshiaki Ohtsu
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  2. Jacqueline A. Gibbons
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  3. Katsuhiro Suzuki
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  4. Michael E. Fitzsimmons
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  5. Kohei Nozawa
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  6. Hiroshi Arai
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Corresponding author

Correspondence to Yoshiaki Ohtsu.

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Funding

Enzalutamide is co-developed by Astellas Pharma Inc and Medivation, Inc. This research was supported by co-developers of enzalutamide, as was the editorial support provided by D. Langer and A. Mason of Infusion Communications.

Conflicts of interest

Yoshiaki Ohtsu, Katsuhiro Suzuki, and Hiroshi Arai are employees of Astellas Pharma. Jacqueline A. Gibbons has declared that she receives stock options as a Medivation employee. Michael E. Fitzsimmons and Kohei Nozawa are employees of Covance and Sekisui, in which the experimental phase of this research was conducted. Other than those mentioned above, the authors report no additional conflicts of interest.

Ethical approval

All in-life portions in this report were conducted in an accredited International Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) facility, which conforms to the Guide for the Care and Use of Laboratory Animals. The protocol was approved by the Astellas Institutional Animal Care and Use Committee. This article does not contain any studies with human participants performed by any of the authors.

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Ohtsu, Y., Gibbons, J.A., Suzuki, K. et al. Absorption, Distribution, Metabolism, and Excretion of the Androgen Receptor Inhibitor Enzalutamide in Rats and Dogs. Eur J Drug Metab Pharmacokinet 42, 611–626 (2017). https://doi.org/10.1007/s13318-016-0374-x

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  • DOI: https://doi.org/10.1007/s13318-016-0374-x

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