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

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.