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

Abstract

Aims: 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). Methods: 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. Results: Steady-state plasma concentrations (mean μM ± 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 μM (95% C.I.: 1.43-6.46) vs 1.67 ± 0.84 μM (95% C.I.: 1.11-2.24), with vs without; while phenytoin-treated patients had lower concentrations: 1.85 ± 0.87 μM (95% C.I.: 1.37-2.34) vs 4.58 ± 5.05 μM (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). Conclusions: There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.