TAMOXIFEN METABOLIC PATTERNS WITHIN A GLIOMA PATIENT POPULATION TREATED WITH HIGH-DOSE TAMOXIFEN

Aims The study was designed to evaluate tamoxifen metabolic profiles i n 25 patients (13 M, 12 F) suffering from recurrent high-grade cerebra l astrocytomas who were treated with high oral doses of tamoxifen (120 mg/m(2) twice daily). Methods Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7 h post dose. Ta moxifen and metabolites were analysed by h.p.l.c. Results Steady-state plasma concentrations (mean mu M +/- s.d.) were determined for tamoxi fen (2.94 +/- 3.44), N-desmethyltamoxifen (4.37 +/- 2.13), N-desdimeth yltamoxifen (1.49 +/- 0.54), 4-hydroxytamoxifen (0.13 +/- 0.95) and ta moxifen 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 mu M (95% C.I. : 1.43-6.46) vs 1.67 +/- 0.84 mu M (95% C.I.: 1.11-2.24), with vs with out; while phenytoin-treated patients had lower concentrations: 1.85 /- 0.87 mu M (95% C.I.: 1.37-2.34) vs 4.58 +/- 5.05 mu M (95% C.I.: 0. 97-8.19), with vs without. The differences approached but did not reac h statistical significance (P = 0.065 and 0.078 respectively). Conclus ions There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the invo lvement of CYP3A in metabolism.