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


CONCLUSIONS
There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.
Ducharme
J
J
Department of Oncology, McGill University, Montreal, Québec, Canada.
Fried
K
K
Shenouda
G
G
Leyland-Jones
B
B
Wainer
I W
IW
D000293:Adolescent; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D001254:Astrocytoma / Q000188:drug therapy / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D013629:Tamoxifen / Q000493:pharmacokinetics* / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating