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Breast Cancer Res Treat (2012) 133:793798 DOI 10.1007/s10549-012-2000-1
BRIEF REPORT
Importance of highly selective LCMS/MS analysisfor the accurate quantication of tamoxifen and its metabolites: focus on endoxifen and 4-hydroxytamoxifen
N. G. L. Jager H. Rosing S. C. Linn
J. H. M. Schellens J. H. Beijnen
Received: 3 February 2012 / Accepted: 15 February 2012 / Published online: 3 March 2012 The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract The antiestrogenic effect of tamoxifen is mainly attributable to the active metabolites endoxifen and 4-hydroxytamoxifen. This effect is assumed to be concentration-dependent and therefore quantitative analysis of tamoxifen and metabolites for clinical studies and therapeutic drug monitoring is increasing. We investigated the large discrepancies in reported mean endoxifen and 4-hydroxytamoxifen concentrations. Two published LCMS/ MS methods are used to analyse a set of 75 serum samples from patients treated with tamoxifen. The method from Teunissen et al. (J Chrom B, 879:16771685, 2011) separates endoxifen and 4-hydroxytamoxifen from other
tamoxifen metabolites with similar masses and fragmentation patterns. The second method, published by Gjerde et al. (J Chrom A, 1082:614, 2005) however lacks selectivity, resulting in a factor 23 overestimation of the endoxifen and 4-hydroxytamoxifen levels, respectively. We emphasize the use of highly selective LCMS/MS methods for the quantication of tamoxifen and its metabolites in biological samples.
Keywords Tamoxifen Endoxifen 4-Hydroxytamoxifen
Metabolite levels LCMS/MS analysis
Introduction
Tamoxifen is widely administered in the treatment and chemoprevention of estrogen receptor positive breast cancer, which accounts for about 6070% of all breast cancers [13]. Tamoxifen is considered to be a prodrug that is converted into many metabolites. The most therapeutically active metabolites are N-desmethyl-4-hydroxytamoxifen (endoxifen) and 4-hydroxytamoxifen, being 30- to 100-fold more potent than tamoxifen itself. The antiestrogenic activities of endoxifen and 4-hydroxytamoxifen are similar, although endoxifen, unlike 4-hydroxytamoxifen, is also a potent inhibitor of aromatase and is present at a higher steady state concentration in patients than 4-hydroxytamoxifen [47].
The steady state levels of the active tamoxifen metabolites are proposed predictors of the clinical outcomes of tamoxifen treatment; it is suggested that there is a minimum concentration threshold above which endoxifen is effective against the recurrence of breast cancer. [8] It is well known from the literature that there is a considerable inter-patient variability in steady...