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.

Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS).

1. Prazosin, 2-[4-(2-furanoyl)-piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, is an antihypertensive agent that has been used safely since 1976 and is currently being investigated for the treatment of post-traumatic stress disorder. The in vivo metabolism of prazosin in rat was first reported in 1977, although at the time analytical techniques were not as sophisticated, nor were the mass spectrometers as sensitive, as today. Recently, the in vitro metabolism of prazosin in rat liver microsomes and cryopreserved hepatocytes was investigated using liquid chromatography/mass spectrometry (LC/MS), which revealed new metabolic pathways. 2. In the present work, rat in vivo metabolism was reinvestigated using a quadrupole time-of-flight mass spectrometer coupled with ultra-performance liquid chromatography, or chip-based nanoflow electrospray ionization, with the aim of identifying metabolites revealed by the in vitro studies and any new metabolites. 3. It is reported that prazosin was metabolized in rats to produce the metabolites observed in vitro. In addition, new phase I metabolites, M18, M20 and M21, were formed and conjugation with glucose or taurine formed the new phase II metabolites, M16 and M19, respectively. 4. Evidence for bioactivation of prazosin included detection of ring-opened metabolites (M4 and M7) and a cysteinyl-glycine conjugate (M17). Further support to the structure of the ring-opened metabolite M7 was obtained by nuclear magnetic resonance (NMR) experiments on M7 isolated from urine.