receptors in the liver, raloxifene has procoagulatory effects, such as decreasing levels of fibrinogen and influencing levels of other coagulation factors. For these reasons, raloxifene increases the risk of thrombosis. Raloxifene 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 raloxifene is approximately 60%. However, due to extensive first-pass metabolism, the absolute bioavailability of raloxifene is only 2.0%. Raloxifene is rapidly absorbed from the intestines upon oral administration. Peak plasma levels of raloxifene occur 0.5 to 6 hours after an oral dose. In healthy postmenopausal women treated with 60 mg/day raloxifene, peak circulating raloxifene 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 Raloxifene is widely distributed throughout the body. There is extensive distribution of raloxifene into the liver, serum, lungs, and kidneys. The volume of distribution of raloxifene 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 raloxifene 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, raloxifene is 98.2 ± 0.4% bound to plasma proteins. Metabolism Raloxifene 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 raloxifene. The metabolites of raloxifene include several glucuronides. The elimination half-life of raloxifene 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 raloxifene is attributed to enterohepatic recirculation and its high plasma protein binding.