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Toremifene, a nonsteroidal triphenylethylene-derivative, is an estrogen agonist-antagonist.
Toremifene is structurally and pharmacologically related to tamoxifen, and the drugs also have been referred to as antiestrogens since they previously were thought to be devoid of clinically important estrogen agonist activity. However, like tamoxifen, toremifene exhibits both estrogen agonist and antagonist (antiestrogen) activity, and the pharmacologic profiles of the 2 drugs are similar. This estrogen agonist and antagonist activity also is shared by several agents with differing chemical structure and pharmacologic activity, such as raloxifene and clomiphene.
The degree of antiestrogenic and/or estrogenic effect of toremifene is influenced by factors such as duration of treatment, target organ, gender, and species; nonsteroidal triphenylethylene derivatives, such as toremifene, generally have a stronger antiestrogenic effect in humans and rats and a mainly estrogenic effect in mice. Toremifene acts as an estrogen antagonist on breast tissue. The antiestrogenic activity of toremifene is demonstrated by a decrease in the estradiol-induced cornification index, which has been observed in some postmenopausal women receiving the drug. Toremifene has weak estrogen-like effects in several sites, including endometrium, bone, and lipids. The estrogenic activity of toremifene has been demonstrated by decreases in serum gonadotropin (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) concentrations.
Toremifene differs from tamoxifen by chlorination of the ethyl side chain, which reduces its antiestrogenic potency and antitumor potency; further study is needed to establish the comparative risk of carcinogenicity (e.g., uterine cancer, hepatocellular cancer) associated with these agents.
•Effects on the Breast
The principal mechanism of toremifene in breast cancer is thought to involve its antiestrogenic effect through competitive binding of the drug to estrogen receptors in the cancer, thus blocking tumor growth stimulated by estrogen. In rats, toremifene has been shown to cause regression of dimethylbenzanthracene-induced mammary tumors. In addition, toremifene may inhibit tumor growth through other mechanisms, such as induction of apoptosis and regulation of oncogene expression and growth factors.
•Effects on Lipoproteins
Limited data indicate that toremifene, like tamoxifen, reduces serum concentrations of total cholesterol and low-density lipoprotein (LDL)-cholesterol. Although toremifene increased serum concentrations of high-density lipoprotein (HDL)-cholesterol in one study, no effect was observed in another study; HDL-cholesterol concentrations appear to be marginally affected by tamoxifen. Long-term studies are needed to determine the effects of toremifene on serum cholesterol concentrations and cardiovascular risk.
•Effects on Bone
The effect of toremifene on bone density and risk of osteoporosis or osteopenia has not been established.
•Effects on the Uterus
Like tamoxifen, toremifene has estrogenic effects on the uterus (i.e., increase in endometrial thickness), and endometrial cancer has been reported in patients receiving toremifene. (See Carcinogenicity: Uterine Cancer in Cautions: Mutagenicity and Carcinogenicity.)
Pharmacokinetics
•Absorption
Toremifene is well absorbed following oral administration. Absorption of the drug is not affected by food. Peak plasma concentrations of toremifene are achieved within 3 hours following oral administration of the drug. Toremifene undergoes enterohepatic circulation. (See Pharmacokinetics: Elimination.) Toremifene displays linear pharmacokinetics after single oral doses of 10–680 mg and dose proportionality after multiple doses of 10–400 mg. Steady-state concentrations of the drug are reached after 4–6 weeks of daily toremifene administration.
•Distribution
The apparent volume of distribution of toremifene is 580 L. The drug binds extensively (greater than 99.5%) to serum proteins, principally albumin. It is not known if toremifene is distributed into milk in humans; however, the drug is distributed into milk in rats. Toremifene has been shown to cross the placenta and accumulate in the fetus in rodents.
•Elimination
Plasma concentrations of toremifene appear to decline in a biphasic manner, with a mean distribution half-life of about 4 hours and a mean elimination half-life of about 5 days. The mean total clearance of toremifene is approximately 5 L/hour.
Toremifene is extensively metabolized in the liver. The drug is metabolized mainly by cytochrome P-450 isoenzyme 3A4 to N-demethyltoremifene, which is antiestrogenic but has weak antitumor potency in vivo. At steady state, serum concentrations of N-demethyltoremifene are 2–4 times higher than those of toremifene. The elimination half-lives of N-demethyltoremifene and (deaminohydroxy) toremifene (another major metabolite) are reported to be 6 and 4 days, respectively.
Toremifene is predominantly excreted in feces as metabolites, with about 10% of an administered dose excreted in urine during a 1-week period. Toremifene undergoes enterohepatic circulation, which contributes to its slow elimination.
The pharmacokinetics of toremifene citrate and N-demethyltoremifene are not altered in patients with renal impairment. The elimination of toremifene is affected by hepatic dysfunction; in 10 patients with hepatic impairment secondary to cirrhosis or fibrosis, the mean elimination half-life of toremifene was increased by less than twofold compared with that in individuals with normal hepatic function. No effect on the pharmacokinetics of N-demethyltoremifene was observed in patients with hepatic impairment.
Increases in the elimination half-life (7.2 versus 4.2 days) and the volume of distribution (627 versus 457 L) compared with values observed in healthy young males were reported in geriatric female patients receiving a single 120-mg dose of toremifene under fasting conditions; however, clearance and area under the plasma concentration-time curve were not altered.
The pharmacokinetics of toremifene have not been evaluated separately by race; 86% of the patients in the North American study were white.
Label Warnings
Lactation
Absolute Contraindication:
ANIMAL STUDIES SUGGEST EXCRETION OCCURS;POTENTIAL SERIOUS ADVER EFF ON INFANT
Pregnancy
Not Recommended
Adverse Effects
Most Frequent:
Drug-Induced Hepatiti, Nausea, Vasomotor Symptoms associated with Menopause
Less Frequent:
Bone Pain, Cataracts, Disorder of Cornea, Dizziness, Dry Eyes, Endometrial Hyperplasia, Glaucoma, Hypercalcemia, Visual Field Defect, Vomiting
Rare:
Acute ST Elevation Myocardial Infarction, Heart Failure, Pulmonary Thromboembolism, Thrombophlebitis, Thrombotic Disorder
Drug-Disease Contraindications
Most Significant
Lactating Mother, Pregnancy, Thromboembolic Disorder
Significant
Endometrial Hyperplasia, Hypercalcemia, Leukopenia, Thrombocytopenic Disorder
