Pharmacodynamics Mechanism of action<unk>  is a selective estrogen receptor modulator (SERM) and hence is a mixed agonist and antagonist of the estrogen receptor (ER) in different tissues. It has estrogenic activity in some tissues, such as bone and the liver, and antiestrogenic activity in other tissues, such as the breasts and uterus. Its affinity (Kd) for the ERα is approximately 50 pM, which is similar to that of estradiol. Relative to estradiol,<unk>  has been reported to possess about 8 to 34% of the affinity for the ERα and 0.5 to 76% of the affinity for the ERβ.<unk>  acts as a partial agonist of the ERα and as a pure antagonist of the ERβ. In contrast to the classical ERs,<unk>  is an agonist of the G protein-coupled estrogen receptor (GPER) ( = 10–100 nM), a membrane estrogen receptor. Clinical effects<unk>  has antiestrogenic effects in the mammary glands in preclinical studies. In accordance,<unk>  reduces breast density in postmenopausal women, a known risk factor for breast cancer. It does not stimulate the uterus in postmenopausal women, and results in no increase in risk of endometrial thickening, vaginal bleeding, endometrial hyperplasia, or endometrial cancer. At the same time,<unk>  has minimal antiestrogenic effect in the uterus in premenopausal women. This may possibly be due to inadequate tissue exposure of the uterus to<unk>  in these estrogen-rich individuals. In premenopausal women,<unk>  increases levels of follicle-stimulating hormone (FSH) and estradiol. Conversely, in postmenopausal women,<unk>  has been found to reduce levels of the gonadotropins, luteinizing hormone (LH) and FSH, while not affecting levels of estradiol.<unk>  also decreases prolactin levels in postmenopausal women. In men,<unk>  has been found to disinhibit the hypothalamic–pituitary–gonadal axis (HPG axis) and thereby increase total testosterone levels. Due to the simultaneous increase in sex hormone-binding globulin (SHBG) levels however, free testosterone levels often remain unchanged in men during therapy with<unk> .<unk>  has estrogenic effects on liver protein synthesis. It increases SHBG levels in both pre- and postmenopausal women as well as in men. The medication decreases levels of total and low-density lipoprotein (LDL) cholesterol, C-reactive protein, apolipoprotein B, and homocysteine. Conversely, it has little effect on levels of triglycerides and high-density lipoprotein (HDL).<unk>  has been shown to inhibit the oxidation of LDL cholesterol in vitro. The medication has been found to decrease insulin-like growth factor 1 (IGF-1) levels in pre- and postmenopausal women as well as in men. It has also been found to increase insulin-like growth factor binding protein 3 (IGFBP-3) levels in pre- and postmenopausal women. Due to activation of estrogen receptors in the liver,<unk>  has procoagulatory effects, such as decreasing levels of fibrinogen and influencing levels of other coagulation factors. For these reasons,<unk>  increases the risk of thrombosis.<unk>  increases bone mineral density in postmenopausal women but decreases it in premenopausal women. In the MORE trial, the risk of vertebral fractures was decreased by 30%, and bone mineral density was increased in the spine (by 2.1% at 60 mg, 2.4% at 120 mg) and femoral neck (2.6% at 60 mg, 2.7% at 120 mg). It has been found to possess estrogenic effects in adipose tissue in postmenopausal women, promoting a shift from an android fat distribution to a gynoid fat distribution. The medication has been found to increase levels of leptin, an adipokine. Pharmacokinetics Absorption The absorption of<unk>  is approximately 60%. However, due to extensive first-pass metabolism, the absolute bioavailability of<unk>  is only 2.0%.<unk>  is rapidly absorbed from the intestines upon oral administration. Peak plasma levels of<unk>  occur 0.5 to 6 hours after an oral dose. In healthy postmenopausal women treated with 60 mg/day<unk> , peak circulating<unk>  levels normalized by dose and body weight were (i.e., divided by (mg/kg)), 0.50 ng/mL (500 pg/mL) after a single dose and 1.36 ng/mL (1,360 pg/mL after multiple doses). Distribution<unk>  is widely distributed throughout the body. There is extensive distribution of<unk>  into the liver, serum, lungs, and kidneys. The volume of distribution of<unk>  with a single 30 to 150 mg oral dose is approximately 2348 L/kg, which corresponds to ~170,000 L for a 72 kg person. Both<unk>  and its glucuronide metabolites show high plasma protein binding (>95%), including to both albumin and α1 acid glycoprotein, but not to sex hormone-binding globulin. More specifically,<unk>  is 98.2 ± 0.4% bound to plasma proteins. Metabolism<unk>  is metabolized in the liver and undergoes enterohepatic recycling. It is metabolized exclusively by glucuronidation and is not metabolized by the cytochrome P450 system. Less than 1% of radiolabeled material in plasma comprises unconjugated<unk> . The metabolites of<unk>  include several glucuronides. The elimination half-life of<unk>  after a single dose is 27.7 hours (1.2 days), whereas its half-life at steady state at a dosage of 60 mg/day is 15.8 to 86.6 hours (0.7–3.6 days), with an average of 32.5 hours (1.4 days). The extended half-life of<unk>  is attributed to enterohepatic recirculation and its high plasma protein binding.<unk>  and its glucuronide conjugates are interconverted by reversible metabolism and enterohepatic recycling, which prolongs the elimination half-life of<unk>  with oral administration. The medication is deconjugated into its active form in a variety of tissues, including liver, lungs, spleen, bone, uterus, and kidneys. Elimination<unk>  is mainly excreted in bile and is eliminated in feces. Less than 0.2% of a dose is excreted unchanged in urine and less than 6% of a dose is excreted in urine as glucuronide conjugates.
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