Determination and Pharmacology of a New Hydroxylated Metabolite of Tamoxifen Observed in Patient Sera during Therapy for Advanced Breast Cancer1

A new hydroxylated metabolite of tamoxifen, Metabolite Y [frans-1 -(p-/?-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene] was characterized and subsequently measured by high-per formance liquid chromatography in serum from patients receiv ing normal (10 mg twice daily) and high dose (>150 mg twice daily) tamoxifen therapy for treatment of advanced breast cancer. In normal-dose patients, the serum level of Metabolite Y ranged between 6 and 60 ng/ml. This contrasted with serum levels of 80 to 180 ng/ml for tamoxifen and 200 to 300 ng/ml for /V-desmethyltamoxifen, the major metabolite of tamoxifen. Serum levels of all three components were unchanged in one patient during the 24 hr after the cessation of tamoxifen ther apy. Maximum serum levels of Metabolite Y were 800 ng/ml with concentrations of 1 /xg/ml for tamoxifen and 2 /¿g/mlfor W-desmethyltamoxifen in a patient on a 2-year course of highdose therapy. Metabolite Y inhibited the binding of 17/S-[3H]estradiol to rat uterine and human breast carcinoma estrogen receptor. However, this metabolite was only weakly active: monohydroxytamoxifen [relative binding affinity (RBA) = 280]; tamoxifen (RBA = 6); Metabolite E (RBA = 3); N-desmethyltamoxifen (RBA = 4); Metabolite Y (RBA = 0.5). In 3day immature rat uterine weight tests, Metabolite Y was a partial agonist with weak antiestrogenic activity. Although Me tabolite Y has only weak activity, this compound would be expected to contribute to the overall antiestrogenic and antitumor properties of tamoxifen during therapy.