title: Distribution of (7alpha)-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(alpha)anthracene-induced mammary tumor.
abstract: (7Alpha)-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(alpha)anthracene-induced mammary carcinoma. The metabolites (7alpha)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol (deEt-TAS-108), (7alpha)-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-[(7alpha)-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, (7alpha)-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.
authors.affiliation: Pharmacokinetics Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Hiraishi, Ebisuno, Kawauchicho, Tokushima 771-0194, Japan. hide-yamaya@taiho.co.jp
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Yamaya
authors.forename: Mayuko
authors.initials: M
authors.lastname: Saeki
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Jiro
authors.initials: J
authors.lastname: Shibata
authors.forename: Shingo
authors.initials: S
authors.lastname: Yano
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takao
authors.forename: Takashi
authors.initials: T
authors.lastname: Shindo
authors.forename: Aman U
authors.initials: AU
authors.lastname: Buzdar
authors.forename: Sekio
authors.initials: S
authors.lastname: Nagayama
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D001943:Breast Neoplasms / Q000139:chemically induced / Q000378:metabolism; D002250:Carbon Radioisotopes; D002277:Carcinoma / Q000139:chemically induced / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004965:Estrogen Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014599:Uterus / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D004965:Estrogen Antagonists; C482068:TS 108; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene