Tamoxifen metabolic patterns within a glioma patient population treated with high-dose tamoxifen

The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13 M, 12 F) suffering from recurrent high-grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120 mg/m2 twice daily).

Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7 h post dose. Tamoxifen and metabolites were analysed by h.p.l.c.

Steady-state plasma concentrations (mean microM +/- s.d.) were determined for tamoxifen (2.94 +/- 3.44), N-desmethyltamoxifen (4.37 +/- 2.13), N-desdimethyltamoxifen (1.49 +/- 0.54), 4-hydroxytamoxifen (0.13 +/- 0.05) and tamoxifen primary alcohol (1.07 +/- 0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone-treated patients than untreated patients: 3.94 +/- 4.35 microM (95% C.I.: 1.43-6.46) vs 1.67 +/- 0.84 microM (95% C.I.: 1.11-2.24), with vs without; while phenytoin-treated patients had lower concentrations: 1.85 +/- 0.87 microM (95% C.I.: 1.37-2.34) vs 4.58 +/- 5.05 microM (95% C.I.: 0.97-8.19), with vs without. The differences approached but did not reach statistical significance (P = 0.065 and 0.078 respectively).

There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.