n-desmethyltoremifene and Breast-Neoplasms

A multicenter phase I pharmacokinetic study of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites. N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1-2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.

Topics: Administration, Oral; Breast Neoplasms; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Drug Administration Schedule; Drug Evaluation; Estrogen Antagonists; Female; Half-Life; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Tamoxifen; Toremifene

To determine whether plasma concentrations of toremifene citrate after administration of 120 mg/day of toremifene citrate given in three separate dose (t.i.d.) were similar to those when toremifene citrate was administered in a single daily doses (40 mg x 3 tablets), we examined changes in plasma concentrations of toremifene citrate (TOR) and its metabolite, N-desmethyltoremifene (TOR-1). In both the t.i.d. administration group and the single-dose administration group, plasma TOR and TOR-1 concentrations reached a constant state within 2 weeks after administration was started. Under the constant state, plasma TOR concentrations were 1,493.3 +/- 120.3 ng/ml in the t.i.d. administration group and 1,348 +/- 341.0 ng/ml in the single-dose administration group. Plasma TOR-1 concentrations were 2,378.3 +/- 186.5 ng/ml in the t.i.d. administration group and 2,144 +/- 475.3 ng/ml in the single-dose administration group. In both groups, plasma TOR-1 concentrations were 2 or more times higher than plasma TOR concentrations. These results show there were no differences in plasma concentrations between administration of 120 mg/day of toremifene citrate in divided daily doses (t.i.d.) and in a single daily dose. The two administration methods appear to produce clinically similar actions.

Topics: Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Administration Schedule; Female; Humans; Middle Aged; Postmenopause; Selective Estrogen Receptor Modulators; Tamoxifen; Toremifene

Toremifene is currently being evaluated as a chemosensitizing agent in doxorubicin-resistant patients. Although concentrations of > 2 microM reverse resistance in vitro, target concentrations required to reverse multidrug resistance (MDR) in vivo may be highly influenced by variables such as protein binding in serum. We examined the effects of high serum concentrations on the cellular accumulation of toremifene in an MDR MDA-MB-A-1 human breast-cancer cell line. We then examined the cellular accumulation of doxorubicin at various toremifene concentrations in 5% - 100% serum. We also measured the concentrations of toremifene and its major metabolites in plasma specimens obtained from two patients receiving 360 mg/day for 5 days in a phase I study. Our results show that (1) high serum concentrations decrease toremifene accumulation, (2) toremifene concentrations of < or = 2.5 microM enhance doxorubicin accumulation, and (3) patients achieve plasma toremifene concentrations of 10-15 microM following doses of 360 mg/day x 5 days. Our findings suggest that in vivo toremifene concentrations well above those used to reverse resistance in vitro are required to overcome the effect of high serum-protein binding.

Topics: Blood Proteins; Breast Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Female; Humans; Protein Binding; Tamoxifen; Toremifene; Tumor Cells, Cultured