@article {Yamaya331, author = {Hidetoshi Yamaya and Mayuko Saeki and Ken-ichiro Yoshida and Jiro Shibata and Shingo Yano and Yoshiaki Sato and Atsushi Takao and Takashi Shindo and Aman U. Buzdar and Sekio Nagayama}, title = {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-DIMETHY{\textellipsis}}, volume = {34}, number = {2}, pages = {331--338}, year = {2006}, doi = {10.1124/dmd.105.005504}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/34/2/331}, eprint = {https://dmd.aspetjournals.org/content/34/2/331.full.pdf}, journal = {Drug Metabolism and Disposition} }