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Drug Metabolism and Disposition Fast Forward
First published on November 18, 2005; DOI: 10.1124/dmd.105.005504

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Received for publication May 16, 2005.
Revised November 7, 2005.
Accepted for publication November 9, 2005.

Distribution of 14C-TAS-108 and Its Metabolites after Single Oral Administration to Rats Bearing DMBA-Induced Mammary Tumor

Hidetoshi Yamaya 1*, Mayuko saeki 1, Ken-ichiro Yoshida 1, Jiro Shibata 1, Shingo Yano 1, Yoshiaki sato 2, Atsushi Takao 2, Takashi Shindo 1, Aman U. Buzdar 3, Sekio Nagayama 1

1 Taiho pharmaceutical Co., Ltd. 2 Daiichi Pure Chemicals Co., Ltd. 3 The University of Texas M. D. Anderson Cancer Center

* Address correspondence to: E-mail: hide-yamaya{at}taiho.co.jp

Abstract

TAS-108 is a novel steroidal anti-estrogen, modulating the differential recruitment of transcriptional co-factors by liganded-ERs, 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 DMBA-induced mammary carcinoma. The metabolites deEt-TAS-108, TAS-108-N-oxide, and TAS-108-COOH were identified as the major metabolites in the plasma; and, additionally, 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 hr 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 AUC 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 OMe-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.


Key words: analytical chemistry, drug development, drug distribution, methylation, pharmacokinetics


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