Estrogen-receptor binding and biologic activity of tamoxifen and its metabolites

In female patients treated with tamoxifen (T), the major metabolite of T in serum is N-desmethyltamoxifen (N-d-Me T). The serum concentration of d-Me T may equal or exceed that of T, and 4-hydroxytamoxifen (4-OH T) is present in much lower concentration (< 10% that of T). The biologic properties and estrogen-receptor binding affinity of T and its desmethyl and 4-hydroxy metabolites have been compared. In competition studies with the rat uterus estrogen receptor at 0 degrees C and 25 degrees C, the relative affinities of T and d-Me T were similar, and their apparent affinity decreased when the incubation temperature was increased (38.2, 21.0 and 1.8, 1.1, respectively at 0 degrees C and 25 degrees C; 17 beta-estradiol = 100). In contrast, 4-OH T was a more potent inhibitor of estradiol binding (110 and 188 at 0 degrees C and 25 degrees C and its apparent affinity increased, rather than decreased, when the incubation temperature was raised from 0 degrees C to 25 degrees C. These differences in receptor binding were not reflected in biologic activity; all three compounds were potent antiestrogens of approximately equal activity in the rat. In patients, the pharmacologic effect of T may be due, in part, to d-Me T, but it is unlikely that 4-OH T plays a major role because of its relatively low serum concentration. The antiestrogenic potencies of T, d-Me T, and 4-OH T are similar, so the extent of metabolism in individual patients is unlikely to influence clinical response to tamoxifen therapy.