Disposition of bazedoxifene in rats

Bazedoxifene acetate (BZA), a novel selective estrogen receptor modulator, is currently being developed for the prevention and treatment of osteoporosis in post-menopausal women. In this study, the disposition of BZA was determined in the rat, a pharmacology and safety model. After a single 0.2 mg/kg intravenous (IV) administration to ovariectomized female rats, the plasma clearance (3.9 L/h/kg) and volume of distribution (16.8 L/kg) of BZA were high and the elimination half-life was short (3.8 h). The bioavailability was low (16%) after a 1 mg/kg oral dose of BZA. Radioactivity was rapidly absorbed (t(max) = 0.35 h), widely distributed into tissues and slowly eliminated (t(1/2) = 29 h) in female rats following a 1 mg/ kg oral dose of [(14)C]BZA. Following a 3 mg/kg oral dose to male rats, the tissue to plasma ratios of radioactivity ranged from 1 to 55 at 2 and 8 h post-dose in ascending order in heart, kidney, lung, and liver. BZA was extensively metabolized in both male and female rats. BZA-5-glucuronide was the major metabolite and BZA-4'-glucuronide was minor in plasma and tissues. Both glucuronides were major metabolites in bile. In vitro metabolite profiles were similar in rat liver and intestinal microsomes and they qualitatively correlated well with bile profiles. Feces was the major route of excretion (>97%) after the IV or oral dose. BZA was the predominant radioactive component in feces.