Metabolic Disposition of [¹⁴C]Bazedoxifene in Healthy Postmenopausal Women

Abstract

ABSTRACT:Bazedoxifene is a selective estrogen receptor modulator under development for the prevention and treatment of osteoporosis. The disposition of [ 14 C]bazedoxifene was determined in six healthy postmenopausal women after administration of a single oral dose of 20 mg (200 Ci). After dosing, blood was collected at frequent intervals, and urine and fecal samples were collected for up to 10 days. Aliquots of plasma, blood, urine, and fecal homogenates were analyzed for concentrations of radioactivity. Bazedoxifene metabolite profiles in plasma and feces were determined by highperformance liquid chromatography with radioactivity flow detection; metabolite structures were confirmed by liquid chromatography-mass spectrometry. Bazedoxifene was rapidly absorbed, exhibiting a mean peak plasma concentration of 3.43 ng/ml at 1.2 h postdose. The total mean recovery of the radioactive dose in excreta was 85.6%, with the majority recovered in feces (84.7%) and only a small fraction (0.81%) in urine. Radiochromatograms of plasma revealed that glucuronidation was the major metabolic pathway; little or no cytochrome P450-mediated metabolism was evident. The majority of circulating radioactivity was constituted by metabolites, with bazedoxifene-5-glucuronide being the predominant metabolite (up to 95%). Bazedoxifene-4-glucuronide was a minor metabolite (up to 20%), and unchanged bazedoxifene represented 0 to 13% of the radioactivity in most plasma samples. Unchanged bazedoxifene was the major radioactive component in feces, however, reflecting unabsorbed drug and/or glucuronides that were hydrolyzed by intestinal bacterial enzymes. [ 14 C]Bazedoxifene was generally well tolerated. These findings demonstrated that, after oral administration in healthy postmenopausal women, bazedoxifene was rapidly absorbed, metabolized via glucuronidation, and excreted predominantly in feces.

Disposition of bazedoxifene in rats

“…Several aspects of the disposition of BZA in rats appear to be similar those observed in post-menopausal women following oral administration (Chandrasekaran et al, 2009). The bioavailability after oral administration was low in both species: approximately 6% in women and 16% in rats.…”

“…Following oral administration of a single 20-mg dose of [ 14 C]bazedoxifene to healthy post-menopausal women, the major route of excretion was the feces (84.7%), with only a minor fraction of the dose (0.8%) eliminated in urine; the predominant metabolic pathway was glucuronidation, with little or no cytochrome P450 metabolism (Chandrasekaran et al, 2009).…”

Treating postmenopausal osteoporosis in women at increased risk of fracture – critical appraisal of bazedoxifene: a review

“…Bazedoxifene is rapidly absorbed50 with a t max of approximately 2 hours and exhibits a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg. Following intravenous administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 ± 3.9 L/kg.…”

Safety, Efficacy and Patient Acceptability of Bazedoxifene Acetate in the Management of Postmenopausal Osteoporosis

“…41,42 Bazedoxifene is little metabolized by cytochrome P450, therefore risk of drug interactions is low. 43 Baird et al 44 evaluated the interaction between bazedoxifene 20 mg and 600 mg ibuprofen, and concluded that the use of two drugs together is safe and does not require dose adjustment.…”