Identification and biological activity of tamoxifen metabolites in human serum.

During the examination of serum samples from patients on chronic 'Nolvadex' therapy three major metabolites (X, Y and Z) were detected in addition to the parent drug. Two of these metabolites have been positively identified as N-desmethyltamoxifen (X) and a side-chain primary alcohol (Y). The third metabolite (Z) has been tentatively identified as N-desdimethyltamoxifen. Quantitative analysis of these metabolites in sera from patients undergoing chronic Nolvadex therapy (20 mg approximately b.d.) has shown that the mean N-desmethyltamoxifen concentration was 481 ng/ml, the mean metabolite Y concentration was 49 ng/ml and that desdimethyltamoxifen concentrations were in the range 20-40 ng/ml. The corresponding mean unchanged drug level in these patients was 310 ng/ml. 4-Hydroxytamoxifen could not be detected in these samples. Measurements of the relative binding affinities of tamoxifen and its metabolites for rat uterus oestrogen receptors have shown that 4-hydroxytamoxifen had a relative binding affinity similar to oestradiol while tamoxifen and its side-chain metabolites had lower affinities. It has been shown that all the metabolites examined are antioestrogenic, as demonstrated by their ability to prevent implantation in pregnant rats and inhibit oestradiol-induced uterine weight gain. It is therefore possible that the metabolites of tamoxifen collectively contribute to the therapeutic activity of the drug.