In vitro metabolism, permeability, and efflux of bazedoxifene in humans.
Article Details
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Shen L, Ahmad S, Park S, DeMaio W, Oganesian A, Hultin T, Scatina J, Bungay P, Chandrasekaran A
In vitro metabolism, permeability, and efflux of bazedoxifene in humans.
Drug Metab Dispos. 2010 Sep;38(9):1471-9. doi: 10.1124/dmd.109.030999. Epub 2010 Jun 1.
- PubMed ID
- 20516255 [ View in PubMed]
- 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 microM for BZA-4'-glucuronide formation and from 2.5 to 11.1 microM for BZA-5-glucuronide formation. V(max) values ranged from 0.8 to 2.9 nmol/(min . mg) protein for BZA-4'-glucuronide and from 0.1 to 1.2 nmol/(min . mg) protein for BZA-5-glucuronide. In Caco-2 cells, BZA appeared to be a P-gp substrate.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Bazedoxifene UDP-glucuronosyltransferase 1-10 Protein Humans UnknownSubstrateDetails Bazedoxifene UDP-glucuronosyltransferase 1-4 Protein Humans UnknownSubstrateDetails Bazedoxifene UDP-glucuronosyltransferase 1-8 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareBazedoxifenePhenytoin The serum concentration of Bazedoxifene can be decreased when it is combined with Phenytoin. BazedoxifeneFosphenytoin The serum concentration of Bazedoxifene can be decreased when it is combined with Fosphenytoin.