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DISTRIBUTION OF (7)-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()ANTHRACENE-INDUCED MAMMARY TUMOR

Pharmacokinetics Research Laboratory (H.Y., M.S., K.Y., T.S., S.N.), Taiho Pharmaceutical Co., Ltd., Tokyo, Japan; Cancer Research Laboratory (J.S., S.Y.), Taiho Pharmaceutical Co., Ltd., Tokyo, Japan; ADME/TOX Research Institute (Y.S., A.T.), Daiichi Pure Chemicals Co., Ltd., Ibaraki, Japan; and The University of Texas M. D. Anderson Cancer Center (A.U.B.), Houston, Texas

(7)-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()anthracene-induced mammary carcinoma. The metabolites (7)-21-[4-[(ethylamino)methyl]-2-methoxyphenoxy]-7-methyl-19-norpregna-1,3,5(10)-trien-3-ol (deEt-TAS-108), (7)-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-[(7)-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, (7)-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 C_max 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.

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