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Research ArticleArticle

DISTRIBUTION OF (7α)-21-[4-[(DIETHYLAMINO) METHYL]-2-METHOXYPHENOXY]-7-METHYL-19-NORPREGNA-1,3,5(10)-TRIEN-3-OL-20-[14C]2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE ([14C]TAS-108) AND ITS METABOLITES AFTER SINGLE ORAL ADMINISTRATION TO RATS BEARING 7,12-DIMETHYLBENZ(α)ANTHRACENE-INDUCED MAMMARY TUMOR

Hidetoshi Yamaya, Mayuko Saeki, Ken-ichiro Yoshida, Jiro Shibata, Shingo Yano, Yoshiaki Sato, Atsushi Takao, Takashi Shindo, Aman U. Buzdar and Sekio Nagayama
Drug Metabolism and Disposition February 2006, 34 (2) 331-338; DOI: https://doi.org/10.1124/dmd.105.005504
Hidetoshi Yamaya
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Mayuko Saeki
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Ken-ichiro Yoshida
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Jiro Shibata
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Shingo Yano
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Yoshiaki Sato
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Atsushi Takao
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Takashi Shindo
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Aman U. Buzdar
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Sekio Nagayama
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Abstract

(7α)-21-[4-[(Diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol 2-hydroxy-1,2,3-propanetricarboxylate (TAS-108) is a novel steroidal antiestrogen, modulating the differential recruitment of transcriptional cofactors by liganded estrogen receptors and representing a promising agent for the treatment of breast cancer. To understand better the relationships between the drug exposure and the efficacy or toxicity of TAS-108, we investigated the metabolism and distribution of TAS-108 after oral administration of [14C]TAS-108 to rats bearing a 7,12-dimethylbenz(α)anthracene-induced mammary carcinoma. The metabolites (7α)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol (deEt-TAS-108), (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol-N-oxide (TAS-108-N-oxide), and 3-methoxy-4-[(7α)-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol-21-yl]oxybenzoic acid (TAS-108-COOH) were identified as the major metabolites in the plasma, and in addition, (7α)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-3-methoxy-7-methyl-19-norpregna-1,3,5(10)-triene (O-Me-deEt-TAS-108) was identified as a novel metabolite in this study. The time-concentration profiles of TAS-108 and its metabolites in the plasma were compared with those in the tumor and uterus of the rats. Radioactivity was found at a high level in various organs including lung, liver, spleen, ovary, and many glands at 12 h and was relatively higher in tumor tissue than in plasma. On the other hand, the levels of radioactivity in the brain and eyeball were very low or not detectable. TAS-108, deEt-TAS-108, and O-Me-deEt-TAS-108 were extensively distributed in the rat tissues and the tumor, with corresponding tissue/plasma ratios for Cmax and area under the curve in the range of 7 to 100. In contrast, TAS-108-COOH and TAS-108-N-oxide were hardly distributed to the tissues and thus may not contribute to the efficacy or toxicity of TAS-108. Thus, TAS-108, deEt-TAS-108, and O-Me-deEt-TAS-108, being distributed highly in tumor tissue, may be more important for the efficacy and toxicity of TAS-108 in vivo than TAS-108-COOH and TAS-108-N-oxide.

Footnotes

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

  • doi:10.1124/dmd.105.005504.

  • ABBREVIATIONS: TAS-108, (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol 2-hydroxy-1,2,3-propanetricarboxylate (SR16234); E2, 17β-estradiol; SERM, selective estrogen receptor modulator; TAT-59, 4-[(E)-1-[4-(dimethylaminoethoxy)]-phenyl)-1-butenyl]phenyl dihydrogen phosphate; TAS-108[M + 4], 20,21-13C2-21,21-D2-labeled TAS-108; [14C]TAS-108, (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol-20-[14C]2-hydroxy-1,2,3-propanetricarboxylate; deET-TAS-108, (7α)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol; TAS-108-N-oxide, (7α)-21-[4-[(diethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol-N-oxide; O-Me-deET-TAS-108, (7α)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-3-methoxy-7-methyl-19-norpregna-1,3,5(10)-triene; SAM, S-adenosyl-l-methionine; HPLC, high-performance liquid chromatography; DMBA, 7,12-dimethylbenz(α)anthracene; LC/MS/MS, liquid chromatography/tandem mass spectrometry; AUC, area under the curve; m/z, mass-to-charge ratio; T/P, tissue/plasma.

    • Received May 15, 2005.
    • Accepted November 9, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (2)
Drug Metabolism and Disposition
Vol. 34, Issue 2
1 Feb 2006
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Research ArticleArticle

DISTRIBUTION OF (7α)-21-[4-[(DIETHYLAMINO) METHYL]-2-METHOXYPHENOXY]-7-METHYL-19-NORPREGNA-1,3,5(10)-TRIEN-3-OL-20-[14C]2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE ([14C]TAS-108) AND ITS METABOLITES AFTER SINGLE ORAL ADMINISTRATION TO RATS BEARING 7,12-DIMETHYLBENZ(α)ANTHRACENE-INDUCED MAMMARY TUMOR

Hidetoshi Yamaya, Mayuko Saeki, Ken-ichiro Yoshida, Jiro Shibata, Shingo Yano, Yoshiaki Sato, Atsushi Takao, Takashi Shindo, Aman U. Buzdar and Sekio Nagayama
Drug Metabolism and Disposition February 1, 2006, 34 (2) 331-338; DOI: https://doi.org/10.1124/dmd.105.005504

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Research ArticleArticle

DISTRIBUTION OF (7α)-21-[4-[(DIETHYLAMINO) METHYL]-2-METHOXYPHENOXY]-7-METHYL-19-NORPREGNA-1,3,5(10)-TRIEN-3-OL-20-[14C]2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE ([14C]TAS-108) AND ITS METABOLITES AFTER SINGLE ORAL ADMINISTRATION TO RATS BEARING 7,12-DIMETHYLBENZ(α)ANTHRACENE-INDUCED MAMMARY TUMOR

Hidetoshi Yamaya, Mayuko Saeki, Ken-ichiro Yoshida, Jiro Shibata, Shingo Yano, Yoshiaki Sato, Atsushi Takao, Takashi Shindo, Aman U. Buzdar and Sekio Nagayama
Drug Metabolism and Disposition February 1, 2006, 34 (2) 331-338; DOI: https://doi.org/10.1124/dmd.105.005504
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