PT - JOURNAL ARTICLE AU - Hidetoshi Yamaya AU - Mayuko Saeki AU - Ken-ichiro Yoshida AU - Jiro Shibata AU - Shingo Yano AU - Yoshiaki Sato AU - Atsushi Takao AU - Takashi Shindo AU - Aman U. Buzdar AU - Sekio Nagayama TI - DISTRIBUTION OF (7α)-21-[4-[(DIETHYLAMINO) METHYL]-2-METHOXYPHENOXY]-7-METHYL-19-NORPREGNA-1,3,5(10)-TRIEN-3-OL-20-[<sup>14</sup>C]2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE ([<sup>14</sup>C]TAS-108) AND ITS METABOLITES AFTER SINGLE ORAL ADMINISTRATION TO RATS BEARING 7,12-DIMETHYLBENZ(α)ANTHRACENE-INDUCED MAMMARY TUMOR AID - 10.1124/dmd.105.005504 DP - 2006 Feb 01 TA - Drug Metabolism and Disposition PG - 331--338 VI - 34 IP - 2 4099 - http://dmd.aspetjournals.org/content/34/2/331.short 4100 - http://dmd.aspetjournals.org/content/34/2/331.full SO - Drug Metab Dispos2006 Feb 01; 34 AB - (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. The American Society for Pharmacology and Experimental Therapeutics