Toremifene metabolism in rat, mouse and human liver microsomes: Identification of α‐hydroxytoremifene by LC‐MS

Abstract The in vitro metabolism of toremifene has been studied in liver microsomal preparations from rat, mouse and human sources using high‐performance liquid chromatography–electrospray ionisation mass spectrometry (HPLC–ESIMS). The metabolites detected were N‐desmethyltoremifene ( m/z 392), 4‐hydroxytoremifene ( m/z 422), 4′‐hydroxytoremifene ( m/z 422) and toremifene N‐oxide m/z 422). In addition, a new polar metabolite with a protonated molecule at m/z 422 has been detected in all three species. The compound was identified by tandem MS‐MS as α‐hydroxytoremifene, an analogue of α‐hydroxytamoxifen. The results showed that α‐hydroxylation is a common feature of tamoxifen and toremifene metabolism and that α‐hydroxytamoxifen is unlikely to be the reactive metabolite responsible for the hepatocarcinogenesis in rat, as widely believed. Copyright © 2002 John Wiley & Sons, Ltd.