A new hydroxylated metabolite of
tamoxifen, Metabolite Y [trans-1-(p-beta-hydroxyethoxyphenyl)-1,2-diphenylbut-1-ene] was characterized and subsequently measured by high-performance liquid chromatography in serum from patients receiving normal (10 mg twice daily) and high dose (greater than or equal to 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
N-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 therapy. Maximum serum levels of Metabolite Y were 800 ng/ml with concentrations of 1 micrograms/ml for
tamoxifen and 2 micrograms/ml for
N-desmethyltamoxifen in a patient on a 2-year course of high-dose
therapy. Metabolite Y inhibited the binding of 17 beta-[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 3-day immature rat uterine weight tests, Metabolite Y was a partial agonist with weak antiestrogenic activity. Although Metabolite Y has only weak activity, this compound would be expected to contribute to the overall antiestrogenic and antitumor properties of
tamoxifen during
therapy.