Optimised analysis of tamoxifen and its main metabolites in the plasma and cytosol of mammary tumours

Abstract

Centre Antoine Lacassagne, 36 voie Romaine, 06054 Nice Cedex, France Summary Recent biochemical and pharmacological findings concerning tamoxifen (TMX) have proven that both the unchanged drug and the main metabolites, N-desmethyltamoxifen (NDT) and 4-hydroxytamoxifen (4 OHT) are biologically active. An HPLC method based on on-line post-column UV irradiation with fluorescence detection is described. Optimized conditions allowed complete and rapid separation of TMX 40HT, NDT and two other recently reported metabolites, Y and Z. This method was applied to plasma and cytosol drug and metabolite analyses. In plasma, from the moment of initial drug administration until the steady state (after 1 month or more of continuous oral TMX treatment), the values of NDT to TMX ratios were completely reversed: 22 to 215 in mean %, P<0.01. The presence of metabolites Y and Z is significant. 40HT, hardly detectable at the first dose, was measured at the steady state with high interpatient variability. It is hypothesized that metabolite evolution with time may be due to auto-induction of drug metabolism. In cytosols, which were all obtained during continuous TMX treatment, the ratios between TMX and metabolites were comparable to those observed in plasma, but with greater interpatient variability. Metabolite Y was not detectable in cytosols. This variability was not linked to the levels of cytosolic oestradiol receptors before initiation of treatment.

Tamoxifen and Metabolite Concentrations in Serum and Breast Cancer Tissue during Three Dose Regimens in a Randomized Preoperative Trial

“…The half-life of tamoxifen has been estimated to be ϳ7 days and that of NDtam 13 days, with near steady-state concentrations being achieved after 4 -6 weeks of continuous treatment (34,42,43). The tamoxifen and metabolite concentrations meas- ured in the present study with doses of 20 mg/day were ϳ40% lower compared with our previous study where tamoxifen had been administered for 2 months (44).…”

Oestrogenic activity of tamoxifen and its metabolites on gene regulation and cell proliferation in MCF-7 breast cancer cells

“…In the absence of endogenous oestrogens, the relative concentrations of these three anti-oestrogens would determine the growth response of the tumour cells. It is also possible that the tumour flare observed in some patients occurs during the transitory period in which tamoxifen or Ndesmethyltamoxifen are present at higher concentrations before the accumulation of significant concentrations of 4-hydroxytamoxifen (Milano et al, 1987).…”

The development of tamoxifen for breast cancer therapy: A tribute to the late Arthur L. Walpole

“…There is usually a blood level ratio of 2 : 1 for N-desmethyltamoxifen: tamoxifen in patients maintained on tamoxifen therapy because N-desmethyltamoxifen has twice the biological half-life of tamoxifen (14 days versus 7 days). The ubiquitous use of tamoxifen in recent years has resulted in the publication of a number of methodologies [69][70][71][72][73][74][75] to estimate tamoxifen and its metabolites in serum. Two minor metabolites, Metabolite Y [76] and Metabolite Z [77], can also be measured by HPLC.…”