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PubMed1990

Biochemical and pharmacological effects of toremifene metabolites.

Toremifene, a new antiestrogenic antitumor compound, has several biologically active metabolites. The hormonal effects of the main metabolites resemble those of unchanged toremifene. The main metabolite in humans, N-demethyltoremifene, is bound to estrogen receptors (ER), inhibits the growth of MCF-7 cells, and exerts an antiestrogenic effect similar to that of toremifene. However, its antitumor effect in vivo against dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancers is weaker than that of toremifene. Didemethyltoremifene has antiestrogenic actions in mouse and rat uterus at high doses. 4-Hydroxytoremifene is bound to ER with higher affinity and inhibits MCF-7 growth at concentrations lower than those of toremifene. It has a weaker intrinsic estrogenic effect than does toremifene. The efficacy of 4-hydroxytoremifene against DMBA-induced cancers is weak except at very high doses. Oxidations of N-demethylated metabolites to (deamino)hydroxylated compounds and carboxylic acids are the detoxification routes of toremifene. (deaminohydroxy)Toremifene has only weak hormonal actions at high doses and carboxylated metabolites have no estrogenic/antiestrogenic effects. The antitumor effect of toremifene in vivo is mainly due to unchanged toremifene, but hormonal effects (which may have a role in antitumor actions) are partly attributable to metabolites N-demethyltoremifene, didemethyltoremifene, (deaminohydroxy)toremifene, 4-hydroxy-N-demethyltoremifene, and 4-hydroxytoremifene, which have pharmacological properties similar to those of toremifene.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1990

Review of the pharmacological properties of toremifene.

New compounds were synthesized with the aim to develop new anti-estrogenic antitumor drugs. The biological properties of the molecules were screened by (1) estrogen receptor (ER) binding, (2) effect on MCF-7 cells, (3) uterotrophic effect and inhibition of estradiol induced uterotropic effect and (4) antitumor effect in DMBA induced rat mammary cancer. One of the molecules, Fc-1157a = toremifene, exhibited the following characteristics: competitive inhibition of [3H]estradiol binding to ER (IC50 = 0.3 mumol/l), inhibition of MCF-7 cell growth in a concentration-dependent manner and cell-killing effect at higher than 3 mumol/l concentrations. Minimal estrogenic dose of toremifene on rat uterus weight was about 40 times higher than that of tamoxifen. Toremifene had statistically significant effect against DMBA-induced rat mammary cancer. Further screening consisted of antitumor, pharmacokinetic and safety studies. Toremifene inhibited the growth of ER-negative, glucocorticoid sensitive, mouse uterine sarcoma in a dose-dependent manner. Pharmacokinetics and metabolism of toremifene resembled closely those of tamoxifen, but since the chlorine atom of the toremifene molecule was not metabolically cleaved tamoxifen and toremifene did not have chemically similar metabolites. Toremifene was well tolerated in animal toxicity studies. No hyperplastic or neoplastic nodules, which were seen in almost all high-dose (48 mg/kg for 24 weeks) tamoxifen-treated rats, were found in toremifene-treated rats (dose 48 mg/kg). In clinical phase I studies in healthy voluntary postmenopausal women, no side effects were reported, at doses less than or equal to 460 mg, neither after a single dose nor after five daily doses. At the dose of 680 mg two out of five persons experienced vertigo and headache. Toremifene, at the dose of 68 mg daily, had antiestrogenic effect on estradiol-induced human vaginal epithelial cells. Clinical phase II studies have confirmed that toremifene has a promising antitumor effect.

Animals↗

PubMed1989

Antiestrogenic action of toremifene on hormone-dependent, -independent, and heterogeneous breast tumor growth in the athymic mouse.

The antiestrogen toremifene has been used to study the growth control of hormone-dependent (MCF-7), -independent (MDA-MB-231), or mixed tumor cell populations in athymic mice. Maximal MCF-7 tumor growth was produced in ovariectomized athymic mice by circulating estradiol levels of approximately 200 pg/ml (produced by 0.5-cm silastic capsules implanted s.c.). The antiestrogen toremifene (77 +/- 4 micrograms/day from a 2-cm silastic capsule) inhibited estradiol (0.5-cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist on the mouse uterus. The growth of hormone-independent MDA-MB-231 breast tumors implanted in athymic mice was not influenced by either estradiol (0.5-cm capsule) or toremifene (2-cm capsule) when administered alone or in combination. Furthermore, even very large doses of toremifene (5 mg/day p.o.) did not alter the rate of MDA-MB-231 tumor growth. Mixtures of MCF-7 and MDA-MB-231 cells in 9:1 and 99:1 ratios inoculated into athymic mice produced tumors which grew in the absence of estradiol but responded to estradiol supplementation (0.5-cm capsule) with a more rapid rate of tumor growth. Tumors grown from inoculated MCF-7:MDA-MB-231 cells (99:1 ratio) in the presence of estradiol had estrogen receptor levels of 33.2 +/- 9.2 fmol/mg of protein at Day 44 compared to 84.8 +/- 4.8 fmol/mg of protein in pure MCF-7 tumors. Toremifene (2-cm capsule) treatment inhibited the estrogen stimulation of these mixed tumors (99:1 starting ratio) to that of toremifene alone. However, toremifene-alone treatment produced a more rapid rate of tumor growth than control or tumors grown from irradiated MCF-7 cells mixed with viable MDA-MB-231 cells. Increasing the ratio of MCF-7:MDA-MB-231 cells (999:1) initially inoculated resulted in tumors which developed less rapidly than the lower ratio (99:1). Toremifene (2-cm capsule) again produced partial inhibition of 17 beta-estradiol-stimulated tumor growth while increasing tumor growth above control when the antiestrogen was administered alone. These results demonstrate that toremifene is effective in inhibiting estrogen stimulation of hormone-dependent tumors and partially successful at controlling mixed hormone-dependent/independent tumors; however, the antiestrogen cannot control the growth of a hormone-independent tumor in this model.

Animals↗

PubMed1990

Preclinical studies with toremifene as an antitumor agent.

Toremifene is a nonsteroidal antiestrogen currently being evaluated for the treatment of breast cancer. Toremifene (10(-10)-10(-6) M) inhibited the growth of MCF-7 breast cancer cells in vitro but was ineffective against hormone-independent MDA-MB-231 cells. This activity was reproduced in vivo using the athymic mouse model. Maximal MCF-7 tumor growth was produced in athymic mice by circulating estradiol levels of approximately 200 pg/ml (from a 0.5 cm silastic capsule implanted sc). Toremifene (77 +/- 44 micrograms/day from a 2 cm silastic capsule) inhibited estradiol (0.5 cm capsule)-stimulated growth by more than 70%. No tumor growth was observed in mice treated with toremifene alone, although toremifene acted as a weak partial agonist and potent antagonist on the mouse uterus. The growth of MDA-MB-231 tumors was not influenced by either estradiol or toremifene. Toremifene (200 micrograms/day) was effective in preventing the development of 7,12-dimethylbenzanthracene-induced rat mammary tumors when given po from day 28 after carcinogen administration. The antitumor activity was reversed if the toremifene was stopped. These findings indicate toremifene is a tumoristatic agent rather than a tumoricidal agent. Clinical trials with toremifene should employ an indefinite treatment strategy to control tumor recurrence in adjuvant studies.

Animals↗

PubMed1992

Monitoring the chemosensitizing effects of toremifene with flow cytometry in estrogen receptor negative multidrug resistant human breast cancer cells.

The clinical study of compounds that modulate multidrug resistance in cancer cells has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at a cellular level. The non-steroidal triphenylethylene toremifene is well tolerated clinically and can sensitize multidrug resistant cells to the effects of doxorubicin in vitro. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-A1 human breast cancer cells were studied using flow cytometric analysis. Cell cycle kinetics of MDA-A1 cells were not significantly affected by treatment with either toremifene or doxorubicin alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene for 70 hours followed by treatment with doxorubicin caused a marked shift of cells to G2, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of doxorubicin alone on doxorubicin-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-A1 cells to doxorubicin. This chemosensitizing effect of toremifene was accompanied by an enhanced accumulation of doxorubicin in MDA-A1 cells (+110% after 70 hours pre-incubation with toremifene), and by a depression in protein kinase C activity in MDA-A1 cells that was maximal following 70 hours incubation with toremifene. Flow cytometry is a widely available technique that might be applied clinically to monitor at the cellular level the chemosensitizing effects of toremifene and other modulators of multidrug resistance.

Breast Neoplasms↗

PubMed1990

Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat.

The effects of toremifene, a new triphenylethylene derivative, on the uterus and DMBA-induced mammary tumors in rats were compared to tamoxifen. The ability of toremifene to compete with [3H]estradiol for cytoplasmic estrogen receptor from rat uterus was similar to tamoxifen, the IC50 being 26 and 23 microM respectively. In immature intact rats the two compounds, administered orally for three consecutive days, had similar intrinsic partial estrogenic efficacy, at 50 mg/kg, about 40% of that of estradiol benzoate (EB). However, at doses less than or equal to 10 mg/kg, the estrogenic effect of toremifene was seen at doses about 40 times higher than that of tamoxifen. The two compounds, administered together with a standard dose of EB, expressed the same maximal antiestrogenic efficacy (about 65% inhibition) at 50 mg/kg. However, the minimal effective antiestrogenic dose of toremifene was about 10 times that of tamoxifen and the ratio between antiestrogenic/estrogenic properties was favourable to toremifene. The duration of the antiestrogenic (antiuterotrophic) effect of a single oral dose (10 mg/kg) of the two compounds proved similar: at least 4 days in intact rats and 3 days in ovariectomized rats. In DMBA-induced tumor bearing rats toremifene was administered p.o., 6 times/week for 4 weeks at 0.08, 0.4, 2, 10 and 50 mg/kg. It was effective at the doses of 2, 10 and 50 mg/kg, inducing 39, 35 and 46% tumor regressions. The activity of toremifene at the minimal effective dose of 2 mg/kg was then compared with that of tamoxifen given at the same dose level. The compounds had comparable activity (47 vs 44% tumor regressions).

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1990

Additive and synergistic antitumor effects with toremifene and interferons.

MFC-7 cells were exposed to toremifene, human alpha and gamma interferons and combinations of them in vitro. Growth of the cells was followed by ATP bioluminescence method. Rats bearing DMBA-induced tumors were treated with toremifene, rat gamma interferon and their combination daily for five weeks. The growth of the tumors was followed by palpation weekly. Toremifene and interferons inhibited the growth of MCF-7 cells. Interferons alpha and gamma were additive; toremifene and interferons were additive or at the best synergistic. Toremifene inhibited the growth of DMBA-induced tumors. Rat gamma interferon alone had no clear effect on the tumor growth. Combination of toremifene and gamma interferone was the most effective treatment and did not show any detectable toxicity. Toremifene and interferons have interesting interactions. Clinical studies using the combination might be warranted.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1990

Enhancement of Adriamycin cytotoxicity in a multidrug resistant Chinese hamster ovary (CHO) subline, CHO-Adrr, by toremifene and its modulation by alpha 1 acid glycoprotein.

The effects of a new antioestrogen, toremifene, on multidrug resistance have been studied in a Chinese hamster ovary parental line, CHO-K1, and in a multidrug resistance subline, CHO-Adrr. Toremifene at subinhibitory concentrations increased the cytotoxic effectiveness of Adriamycin in both cell lines. The degree of potentiation was greater in the CHO-Adrr lines for any given concentration of toremifene. Toremifene is 99.7% bound to human serum proteins (Sipila et al. Pharmacol Toxicol 1988, 63, 62-64), which includes binding to an acute phase plasma protein, alpha 1 acid glycoprotein (AAG). Since AAG is normally absent from tissue culture media, we have assessed the effect of AAG on toremifene mediated potentiation of Adriamycin cytotoxicity. In the presence of increasing concentrations of AAG, there was a dose-related reversal of the effect of toremifene on Adriamycin cytotoxicity in both cell lines. These results show that toremifene is effective in enhancement of Adriamycin cytotoxicity in CHO-K1 and CHO-Adrr cell lines, and this modulation can be altered by AAG. The clinical implication is that patients should be selected for such therapy by measurement of AAG levels.

Animals↗

PubMed1989

Toremifene: pharmacologic and pharmacokinetic basis of reversing multidrug resistance.

Triphenylethylene compounds, such as tamoxifen, have shown chemosensitizing activity independent of estrogen receptor status in doxorubicin-resistant cells. We examined the chemosensitizing activity of a new triphenylethylene, toremifene, and its major metabolites in a doxorubicin-resistant human breast cell line, MCF-7/DOX. In addition, we examined the chemosensitizing activity of unbound plasma toremifene and its metabolites isolated from patients treated with toremifene doses of 20 to 400 mg/d. MCF-7/DOX cells were exposed to ultrafiltrate plasma specimens in the absence and presence of doxorubicin. These latter studies were single-blinded. Toremifene and its major metabolites were capable of sensitizing multidrug-resistant cells to doxorubicin. The degree of chemosensitizing activity in vitro correlated with the plasma concentrations of toremifene and its metabolites (P less than .05). Plasma samples isolated from patients receiving high-dose toremifene (400 mg/d) had the greatest chemosensitizing activity. We present evidence that toremifene and its metabolites can sensitize resistant MCF-7/DOX cells to doxorubicin, that this effect is concentration-dependent, and that sensitizing activity can be detected at clinically achieved concentrations.

Blood↗

PubMed1990

Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer.

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.

Administration, Oral↗

PubMed1992

Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells.

The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50 = less than 0.1 microgram/ml MDA 231; IC 50 = 100 micrograms/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed1990

Phase III studies of toremifene in metastatic breast cancer.

Toremifene has proven to be an effective and well tolerated antiestrogenic compound in the treatment of locally advanced and metastatic breast cancer. Results of phase II studies reveal that the efficacy using a 60 mg daily dose is comparable to tamoxifen. Since toremifene is less toxic in high doses than tamoxifen, in many clinical studies greater than or equal to 200 mg daily doses are used. For more accurate comparison of toremifene and tamoxifen five different clinical phase III studies have been initiated. By December 1, 1989, there were altogether 650 patients accrued into these studies. Two of the studies are double blind comparison of the drugs, one conducted in Finland, Sweden, and Norway, and the other in Denmark. Three open studies are going on, one in the Soviet Union, one in West Germany (BRD), and the third in the USA and Canada. To clarify dose-dependency of toremifene action, a daily dose from 60 mg up to 240 mg is used in these studies compared to 20-40 mg daily doses of tamoxifen. The results of these studies are still too early for critical evaluation, since in the double blind studies no interim comparison of the drugs is possible, and the results of the BRD and USA-Canada open studies will not be analyzed before sufficient patients for statistical evaluation have been included. Preliminary results of the Soviet trial comparing 60 and 240 mg toremifene doses with 40 mg of tamoxifen show that the response rate is highest in the 240 mg toremifene arm, although there are no statistically significant differences. Statistical significance in clinical studies like these is an important aspect of reliability, which based on trial protocols will be critically evaluated and discussed.

Antineoplastic Agents↗

PubMed1992

Chemosensitizing effect of an antiestrogen, toremifene, on ovarian cancer.

The chemosensitizing effect of an antiestrogen, toremifene, was studied on 2 human ovarian cancer cell lines in vitro and on 3 fresh surgical ovarian tumor explants with the aid of the subrenal capsule assay (SRCA). Also, 11 patients with secondarily drug resistant, recurrent gynecologic cancer (8 ovarian and 3 uterine cancers) were treated with 240 mg toremifene daily for 1 week before each course of cytostatics. Toremifene potentiated the effect of doxorubicin on both cell lines. This was also the case on 1 cell line that was not completely resistant to doxorubicin. The SRCA showed a clear potentiating effect of toremifene only on the tumor overtly resistant to the combination of cisplatin, doxorubicin, and cyclophosphamide. Of the 11 patients treated with toremifene and cytostatics, the response of 8 patients was evaluable: 3 had partial response, 3 no change, and 2 progressive disease. Toremifene seems to have a chemopotentiating effect on gynecologic drug-resistant tumors.

Aged↗

PubMed1988

Binding of toremifene to human serum proteins.

The in vitro protein binding of toremifene in human serum was measured by ultracentrifugation using 3H-toremifene together with unlabeled toremifene, 50, 500, and 5000 ng/ml. Of the total radioactivity 99.7 per cent was bound to the proteins independent of the concentration of the unlabeled drug. Binding of toremifene to different protein fractions was studied by adding 3H-toremifene and 500 ng/ml of cold toremifene to normal serum. The serum samples were exposed to agarose gel electrophoresis to fractionate different proteins. The radioactivity was localized using a position-sensitive proportional counter. After that the proteins were visualized by staining. Of the total protein bound radioactivity 92 per cent was bound to albumin, about 6 per cent to beta 1 globulin fraction and about 2 per cent to a fraction between albumin and alpha 1 globulins, part of this probably to alpha 1 acid glycoprotein.

Blood Proteins↗

PubMed1992

Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer.

Toremifene is an antiestrogen that binds strongly to estrogen receptors (ER). A total of 19 previously treated postmenopausal women with metastatic breast cancer whose performance status was good and whose ER status was positive or unknown were studied to determine the maximum tolerated dose of toremifene. Cohorts of patients received 200, 300, or 400 mg/m2 p.o. daily until relapse or unacceptable toxicity had occurred. Nausea, vomiting, and dizziness were dose-related. Three of five patients receiving 400 mg/m2 experienced moderate or severe vomiting and another developed reversible disorientation and hallucinations. Mild sweating, peripheral edema, vaginal discharge, and hot flushes were encountered at all doses. Reversible corneal pigmentation was identified in seven cases but was not of clinical importance. The pharmacokinetics of toremifene was studied weekly and in detail on day 42 using a high-performance liquid chromatographic (HPLC) assay that identified the parent compound and three active metabolites, N-desmethyltoremifene, (deaminohydroxy)toremifene, and didemethyltoremifene. Steady state was achieved at 1-3 weeks. The toremifene area under the curve and the maximal concentration were dose-dependent at high doses. The recommended phase II dose is 300 mg/m2 p.o. daily.

Adult↗

PubMed1990

Phase II trials with toremifene in advanced breast cancer: a review.

The antitumor activity of the new triphenylethylene drug toremifene has been studied in advanced breast cancer of postmenopausal women as first line treatment at dose levels of 20, 60, and 240 mg, and as second line or later treatment at high dose levels of 200-240 mg. The response rates (complete + partial response) have been 21% with 20 mg (14 patients), 52% with 60 mg (93 patients in three separate trials), and 68% with 240 mg (38 patients) as first line treatment. After failure on previous therapy (hormonal or chemotherapy) the response rates have been about 10% with 200 mg of toremifene (71 patients in two different trials). In patients whose disease had previously responded to tamoxifen with at least stabilization, the response rate with toremifene has been 23%; but among unselected patients, including patients progressing during adjuvant tamoxifen, the response rate (CR + PR) with toremifene in tamoxifen failures has been 3%. If long lasting (more than 5 months) stabilization of the disease is also considered, a further 20% of previously treated patients have benefitted from toremifene. The treatment has been well tolerated at all dose levels. The most reported side effects have been hot flushes (8-19%) and nausea (8%). 0-6% of patients in different trials have interrupted the treatment because of side effects.

Antineoplastic Agents↗

PubMed1990

Inhibition of hormone-dependent and independent breast cancer cell growth in vivo and in vitro with the antiestrogen toremifene and recombinant human interferon-alpha 2.

The antiproliferative action of the antiestrogen toremifene and recombinant human interferon-alpha 2a (IFN-alpha 2a) were examined on human breast cancer cell lines grown in culture and in the athymic mouse. Solid tumors grew from an inoculation of a 99:1 ratio of hormone dependent (MCF-7) and hormone independent (MDA-MB-231) breast cancer cells without estrogen administration. However, estradiol supplementation significantly increased the rate of tumor growth. The daily administration of 1.35 x 10(6) U of recombinant human IFN-alpha 2a resulted in a marked rduction of tumor growth in both estradiol-treated and non-treated mice. Toremifene administration (130 micrograms/day from a sustained release preparation) markedly inhibited estradiol stimulation of mouse uterine weight and partially reduced estradiol-stimulated tumor growth. The combination of IFN-alpha 2a (1.35 x 10(6) u/day) with toremifene (130 micrograms/day) reduced estradiol-stimulated growth much below that of toremifene alone but not below that seen with interferon alone. Toremifene (10(-10)-10(-6) M) did not inhibit the growth of hormone-independent MDA-MB-231 breast cancer cells in vitro whereas it did inhibit the growth of hormone-dependent MCF-7 cells in phenol red containing media. IFN-alpha 2a (1-10,000 u) inhibited the growth of both MCF-7 and MDA-MB-231 cells in culture; however, MCF-7 cells were approximately 10-fold more sensitive to interferon inhibition. This was consistent with the MCF-7 cells showing a greater sensitivity to interferon than MDA-MB-231 cells in the induction of 2'5'-oligoadenylate synthetase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Pharmacokinetics of toremifene.

The pharmacokinetics of toremifene has been investigated in man after single and multiple oral doses. Toremifene was completely absorbed without first-pass metabolism. Peak concentration in serum was achieved in 4 h. Mean half-lives of distribution and elimination were 4 h and 5 days, respectively. Kinetics was linear in the studied dose-range of 10-680 mg. Toremifene was over 99% bound to plasma proteins and extensively metabolized. The main metabolites in serum were demethyl- and deaminohydroxytoremifene. In patients receiving multiple dosing of 60 mg/day serum steady-state level of toremifene was 0.8 microgram/ml on average. The level of demethyl metabolite was twice and that of deaminohydroxy metabolite was one tenth of toremifene.

Biological Availability↗