Bazedoxifene: A Third-Generation Selective Estrogen Receptor Modulator for Treatment of Postmenopausal Osteoporosis

Stump, Amy L.; Kelley, Kristi W.; Wensel, Terri M.

doi:10.1345/aph.1h428

Cited by 24 publications

(27 citation statements)

References 9 publications

(12 reference statements)

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“…BZA did not stimulate the uterine endometrium in women at dosages up to 40 mg, correlating well with the preclinical pharmacology (Miller et al, 2002;Ronkin et al, 2005;Lewiecki, 2007). BZA represents a promising pharmacotherapy against osteoporosis with a potentially enhanced safety profile (Stump et al, 2007). Both preclinical and clinical data indicated that BZA has a unique combination of attributes, making it an attractive option for the treatment and prevention of osteoporosis (Gennari et al, 2007(Gennari et al, , 2008.…”

Section: Introductionsupporting

confidence: 56%

In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans

Shen

Ahmad²,

Park³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Bazedoxifene (BZA) acetate, a novel estrogen receptor modulator being developed for the prevention and treatment of postmenopausal osteoporosis, undergoes extensive metabolism in women after oral administration. In this study, the in vitro metabolism of [ 14 C]BZA was determined in human hepatocytes and hepatic and intestinal microsomes, and the UDP glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of BZA were identified. In addition, BZA was evaluated for its potential as a substrate of P-glycoprotein (P-gp) transporter in Caco-2 cell monolayers. BZA was metabolized to two monoglucuronides, BZA-4-glucuronide and BZA-5-glucuronide, in hepatocytes and in liver and intestinal microsomes including jejunum, duodenum, and ileum. Both BZA-4-glucuronide and BZA-5-glucuronide were major metabolites in the intestinal microsomes, whereas BZA-4-glucuronide was the predominant metabolite in liver microsomes and hepatocytes. The kinetic parameters of BZA-4-glucuronide formation were determined in liver, duodenum, and jejunum microsomes and with UGT1A1, 1A8, and 1A10, the most active UGT isoforms involved in the glucuronidation of BZA, whereas those of BZA-5-glucuronide were determined with all the enzyme systems except in liver microsomes and in UGT1A1 because the formation of the BZA-5-glucuronide was too low. K m values in liver, duodenum, and jejunum microsomes and UGT1A1, 1A8, and 1A10, were similar and ranged from 5.1 to 33.1 M for BZA-4-glucuronide formation and from 2.5 to 11.1 M for BZA-5-glucuronide formation. V max values ranged from 0.8 to 2.9 nmol/(min ⅐ mg) protein for BZA-4-glucuronide and from 0.1 to 1.2 nmol/(min ⅐ mg) protein for BZA-5-glucuronide. In Caco-2 cells, BZA appeared to be a P-gp substrate.

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Section: Introductionsupporting

confidence: 56%

In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans

Shen

Ahmad²,

Park³

et al. 2010

Drug Metab Dispos

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“…None of these subjects had any illnesses at baseline that might have interfered with the pharmacokinetics of the test article or the interpretation of the results. In postmenopausal women, bazedoxifene given at 20 mg/day has been shown to decrease bone turnover by 20 to 25%, with no occurrences of endometrial hyperplasia (Gruber and Gruber, 2004;Ronkin et al, 2005;Stump et al, 2007). Bazedoxifene displayed straightforward pharmacokinetic properties after a single oral dose of [ 14 C]bazedoxifene in this study.…”

Section: Discussionmentioning

confidence: 57%

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

Chandrasekaran¹,

McKeand²,

Sullivan³

et al. 2009

Drug Metab Dispos

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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.

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“…When estrogen is deficient, bone turnover increases, and bone resorption increases more than bone formation, leading to bone loss (Gennari et al, 2006;Maximov et al, 2013;Riggs & Hartmann, 2003;Stump et al, 2007). Bazedoxifene and lasofoxifene belong to the classes of SERMs, which exhibit estrogen agonist activity in some target tissues while exert estrogen antagonist activity in other tissues (Gennari et al, 2006;Maximov et al, 2013;Riggs & Hartmann, 2003;Stump et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Based on the timing of their clinical development, SERMs can be divided into three generations: 1) Tamoxifen, a triphenylethlene, is considered a first generation SERM (Maximov et al, 2013;Riggs & Hartmann, 2003), 2) Raloxifene, a benzothiophene, is a member of second generation SERMs (Maximov et al, 2013;Riggs & Hartmann, 2003), 3) Third generation SERMs are typified by indole-based bazeoxifene (Maximov et al, 2013;Riggs & Hartmann, 2003;Stump, Kelley, & Wensel, 2007) and napthalene derivative lasofoxifene (Gennari, Merlotti, Martini, & Nuti, 2006;Maximov et al, 2013;Riggs & Hartmann, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Tamoxifen is prescribed frequently for the prevention and treatment of breast cancer, and raloxifene is used mainly for the prevention and treatment of osteoporosis in post-menopausal women (Maximov et al, 2013;Riggs & Hartmann, 2003). In 2009, third generation SERMs bazedoxifene and lasofoxifene were approved for use in the Europe to prevent and treat post-menopausal osteoporosis under the trade names Conbriza and Fablyn, respectively (Gennari et al, 2006;Maximov et al, 2013;Riggs & Hartmann, 2003;Stump et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Bazedoxifene: A Third-Generation Selective Estrogen Receptor Modulator for Treatment of Postmenopausal Osteoporosis

Cited by 24 publications

References 9 publications

In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans

In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans

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

Searching for novel ligands for the cannabinoid and related receptors.

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Bazedoxifene: A Third-Generation Selective Estrogen Receptor Modulator for Treatment of Postmenopausal Osteoporosis

Cited by 24 publications

References 9 publications

In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans

In Vitro Metabolism, Permeability, and Efflux of Bazedoxifene in Humans

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

Searching for novel ligands for the cannabinoid and related receptors.

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