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Research ArticleArticle

Absorption, Metabolism and Excretion of [14C]Mirabegron (YM178), a Potent and Selective β3-Adrenoceptor Agonist, after Oral Administration to Healthy Male Volunteers

Shin Takusagawa, Jan Jaap van Lier, Katsuhiro Suzuki, Masanori Nagata, John Meijer, Walter Krauwinkel, Marloes Schaddelee, Mitsuhiro Sekiguchi, Aiji Miyashita, Takafumi Iwatsubo, Marcel van Gelderen and Takashi Usui
Drug Metabolism and Disposition April 2012, 40 (4) 815-824; DOI: https://doi.org/10.1124/dmd.111.043588
Shin Takusagawa
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Jan Jaap van Lier
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Katsuhiro Suzuki
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Masanori Nagata
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John Meijer
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Walter Krauwinkel
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Marloes Schaddelee
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Mitsuhiro Sekiguchi
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Aiji Miyashita
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Takafumi Iwatsubo
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Marcel van Gelderen
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Takashi Usui
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Abstract

The mass balance and metabolite profiles of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)[U-14C]phenyl]acetamide ([14C]mirabegron, YM178), a β3-adrenoceptor agonist for the treatment of overactive bladder, were characterized in four young, healthy, fasted male subjects after a single oral dose of [14C]mirabegron (160 mg, 1.85 MBq) in a solution. [14C]Mirabegron was rapidly absorbed with a plasma tmax for mirabegron and total radioactivity of 1.0 and 2.3 h postdose, respectively. Unchanged mirabegron was the most abundant component of radioactivity, accounting for approximately 22% of circulating radioactivity in plasma. Mean recovery in urine and feces amounted to 55 and 34%, respectively. No radioactivity was detected in expired air. The main component of radioactivity in urine was unchanged mirabegron, which accounted for 45% of the excreted radioactivity. A total of 10 metabolites were found in urine. On the basis of the metabolites found in urine, major primary metabolic reactions of mirabegron were estimated to be amide hydrolysis (M5, M16, and M17), accounting for 48% of the identified metabolites in urine, followed by glucuronidation (M11, M12, M13, and M14) and N-dealkylation or oxidation of the secondary amine (M8, M9, and M15), accounting for 34 and 18% of the identified metabolites, respectively. In feces, the radioactivity was recovered almost entirely as the unchanged form. Eight of the metabolites characterized in urine were also observed in plasma. These findings indicate that mirabegron, administered as a solution, is rapidly absorbed after oral administration, circulates in plasma as the unchanged form and metabolites, and is recovered in urine and feces mainly as the unchanged form.

Footnotes

  • This study was sponsored by Astellas. The editorial support was funded by Astellas.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.043588.

  • ABBREVIATIONS:

    YM178
    2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, mirabegron
    OAB
    overactive bladder
    AUC
    area under the concentration-time curve
    IS
    internal standard
    HPLC
    high-performance liquid chromatography
    LC
    liquid chromatography
    RAD
    radiochemical detector
    LSC
    liquid scintillation counter
    MS
    mass spectrometry
    ROESY
    rotational nuclear Overhauser effect spectroscopy
    ROE
    rotational nuclear Overhauser effect.

  • Received October 28, 2011.
  • Accepted January 23, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

ABSORPTION, METABOLISM, AND EXCRETION OF MIRABEGRON

Shin Takusagawa, Jan Jaap van Lier, Katsuhiro Suzuki, Masanori Nagata, John Meijer, Walter Krauwinkel, Marloes Schaddelee, Mitsuhiro Sekiguchi, Aiji Miyashita, Takafumi Iwatsubo, Marcel van Gelderen and Takashi Usui
Drug Metabolism and Disposition April 1, 2012, 40 (4) 815-824; DOI: https://doi.org/10.1124/dmd.111.043588

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Research ArticleArticle

ABSORPTION, METABOLISM, AND EXCRETION OF MIRABEGRON

Shin Takusagawa, Jan Jaap van Lier, Katsuhiro Suzuki, Masanori Nagata, John Meijer, Walter Krauwinkel, Marloes Schaddelee, Mitsuhiro Sekiguchi, Aiji Miyashita, Takafumi Iwatsubo, Marcel van Gelderen and Takashi Usui
Drug Metabolism and Disposition April 1, 2012, 40 (4) 815-824; DOI: https://doi.org/10.1124/dmd.111.043588
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