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

Abstract

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.

Quantitative Prediction of Human Intestinal Glucuronidation Effects on Intestinal Availability of UDP-Glucuronosyltransferase Substrates Using In Vitro Data

“…For example, for raloxifene, the glucuronidation rates of UGT1A8, UGT1A9, and UGT1A10 are reported to be higher than those of other isoforms (Kemp et al, 2002), which is consistent with our remaining ratio results. Similar consistencies were found with bazedoxifene for UGT1A1, UGT1A8, and UGT1A10 (Shen et al, 2010), diclofenac and gemfibrozil for , and 25.5 ml ⅐ min Ϫ1 ⅐ kg Ϫ1 (C). Solid lines were obtained by fitting with the nonlinear least-squares method.…”

“…However, the predicted concentrations in human intestine (Supplemental Data 3) were much higher than 0.1 M, indicating that intestinal glucuronidation should be saturated, which contradicts the linearity of oral AUC increases. For example, a previous study found that K m values of bazedoxifene for intestinal microsomes-5.1 (bazedoxifene-4Ј-glucuronide) and 5.1 M (bazedoxifene-6Ј-glucuronide) (Shen et al, 2010)-were lower than the predicted intestinal concentration (25-170 M) at oral doses ranging from 3 to 20 mg (Supplemental Data 3); however, oral AUC values were reported to increase in proportion to oral doses from 5 to 120 mg (Supplemental Data 2). This contradiction may be explained by autoactivation and gut volume.…”

Drug Disposition and Drug-Drug Interaction Data in 2013 FDA New Drug Applications: A Systematic Review

“…In the case of eslicarbazepine acetate, in vivo drug interaction studies were preemptively performed with two known P-gp inhibitors, cyclosporine and verapamil, and no interaction was observed in either study. For bazedoxifene, in vitro screening studies have been published previously (Shen et al, 2010), thus no studies were included in the filing. Out of the 12 positive P-gp in vitro results, 7 in vivo studies were performed, with the largest interaction observed in the case of sofosbuvir (AUC ratio = 3.6, when coadministered with cyclosporine).…”

Novel Ligands Balance Estrogen Receptor β and α Agonism for Safe and Effective Suppression of the Vasomotor Response in the Ovariectomized Female Rat Model of Menopause

“…A combination of conjugated estrogens with bazedoxifene has been evaluated in a 2-year clinical trial and found to be effective in treatment of hot flushes without untoward effects to date (51). Bazedoxifene does not stimulate the proliferation of MCF-7 cells, although it has a very low bioavailability relative to conjugated estrogens (52), and long-term effects on breast tissue are not known.…”