Metabolism of tamoxifen and its uterotrophic activity

Tamoxifen is an estrogen agonist in mouse uterus, a partial estrogen agonist/antagonist in rat uterus, and a pure estrogen antagonist in chicken oviduct. Tamoxifen metabolism was examined both in vitro and in vivo to determine if differences in the species response to this drug resulted from the differential formation of metabolites with estrogenic or antiestrogenic activity. Animals were given a subcutaneous injection of [³H]tamoxifen, and 4 or 24 hr later tamoxifen and its metabolites were extracted from tissues and separated by TLC. The profiles of metabolites extracted from livers of these species were qualitatively similar; the principle metabolite was 4-hydroxytamoxifen, which comprised 27, 14, and 16% of the radioactivity from mouse, rat, and chicken livers, respectively, at 24 hr. Tamoxifen, however, was the principal compound extracted from all three livers. Metabolites extracted from mouse and rat uteri were the same ones obtained from liver, although their abundance (relative to tamoxifen) was much lower in uteri than in liver. Metabolite E and bisphenol, two tamoxifen derivatives that we believed might account for the uterotrophic effect of tamoxifen in the mouse, were found not to be formed in either liver or uterus. Tamoxifen metabolism was also studied in vitro using liver microsomes from these same species; The same metabolites were formed in vitro as in vivo, although their relative abundances were lower in vitro. No clear-cut differences in metabolism were seen that would account for the disparate pharmacological effects of tamoxifen in these species.