IDENTIFICATION OF TAMOXIFEN METABOLITES IN HUMAN HEP G2 CELL-LINE, HUMAN LIVER HOMOGENATE, AND PATIENTS ON LONG-TERM THERAPY FOR BREAST-CANCER

The metabolism of tamoxifen was examined in human liver homogenate and human Rep G2 cell line preparations by LC/electro spray ionization/MS . Several metabolites were detected in the human liver homogenate extr acts, namely N-didesmethyltamoxifen (metabolite I), alpha-hydroxytamox ifen (metabolite II), 4-hydroxytamoxifen (metabolite III), N-desmethyl tamoxifen (metabolite IV), and tamoxifen N-oxide (metabolite V). Metab olites II, III, IV, and V were observed in the samples after incubatin g tamoxifen with the human Rep G2 cell line. When these results were c ompared with the metabolic profiles in patients, apart from metabolite s I-V, alpha-hydroxy-N-desmethyltamoxifen (VI) and 4-hydroxy N-desmeth yltamoxifen (VII) were present in all the plasma samples, In addition, in patients who had received tamoxifen treatment daily for >6 months, several minor metabolites were detected, namely 4-hydroxytamoxifen N- oxide (metabolite VIII) and two dihydroxylated analogs (metabolites IX and X). The precise positions of the hydroxylation have yet to be det ermined.