Tamoxifen dosage is based on the one-dose-fits-all approach. The anticancer effect of
tamoxifen is believed to be due to the metabolites,
4-hydroxytamoxifen (4OHtam), and
4-hydroxy-N-desmethyltamoxifen (4OHNDtam/
endoxifen). These demethylated metabolites of
tamoxifen have been associated with its side effects, whereas the effect mediated by
tamoxifen-N-oxide (tamNox) is still poorly understood. Our objective was to improve the therapeutic index of
tamoxifen by personalizing its dosage and maintaining serum
tamoxifen metabolite concentrations within a target range. We examined the levels of
tamoxifen, 4OHtam, 4OHNDtam,
N-desmethyltamoxifen (NDtam), N-
desdimethyltamoxifen (NDDtam), and tamNox in serum and in
breast tumors specimens of 115 patients treated with 1, 5 or 20 mg/day of
tamoxifen for 4 weeks before surgery in a randomized trial. Furthermore, the metabolism of tamNox in MCF-7
breast cancer cells was also studied. The concentrations of
tamoxifen and its metabolites in
tumor tissues were significantly correlated to their serum levels.
Tumor tissue levels were 5-10 times higher than those measured in serum, with the exception of tamNox. In MCF-7 cells, tamNox was converted back to
tamoxifen. In contrast to the tissue distribution of tamNox, the concentrations of 4OHtam and 4OHNDtam in
tumor tissues corresponded to their serum levels. The results suggest that implementation of therapeutic
drug monitoring may improve the therapeutic index of
tamoxifen. Furthermore, the tissue distribution of tamNox deviated from that of the other
tamoxifen metabolites.