In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1Hindol- 5-ol in human liver microsomes
Trdan Lušin, Tina (Author), Tomašič, Tihomir (Author), Trontelj, Jurij (Author), Mrhar, Aleš (Author), Peterlin-Mašič, Lucija (Author)

URLURL - Presentation file, Visit http://www.sciencedirect.com/science/article/pii/S0009279712000312?v=s5 This link opens in a new window

Bazedoxifene is a selective estrogen receptor modulator (SERM) that has been developed for use in post-menopausal osteoporosis. However, it contains a potentially toxic 5-hydroxy-3-methylindole moiety. Previous studies on the 5-hydroxyindole and the 3-alkylindole-containing drugs indometacine, zafirlukast and MK-0524 structural analogs have shown that they are bioactivated by cytochrome P450s through a dehydrogenation process to form quinoneimine or 3-methyleneindolenine electrophilic species. In the present study, bazedoxifene was synthesized and then evaluated, together with raloxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (13), a 3-methyl-5-hydroxyindole-based structural fragment of bazedoxifene, for its ability to form reactive electrophilic species when incubated with human liver microsomes (HLM) or recombinant CYP isozymes. We showed that bazedoxifene was bioactivated only in trace amounts with recombinant CYP isozymes. In contrast, the N-dealkylated fragment of bazedoxifene (2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) was bioactivated in considerable amounts to an electrophilic intermediate, which was trapped with glutathione and identified by LC-MS/MS. This suggests that bazedoxifene would require initial N-dealkylation, which could subsequently lead to the formation of the reactive intermediate. However, such an N-dealkylated metabolite of bazedoxifene was not detected after the incubation of bazedoxifene in HLM or recombinant CYP isozymes.

Keywords:bazedoksifen, raloksifen, LC-MS/MS, citokrom P450, osteporoza
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:str. 8-15
Numbering:Vol. 197, issue 1
ISSN on article:0009-2797
DOI:10.1016/j.cbi.2012.03.001 Link is opened in a new window
COBISS.SI-ID:3213425 Link is opened in a new window
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Record is a part of a journal

Title:Chemico-biological interactions
Shortened title:Chem.-biol. interact.
COBISS.SI-ID:1720335 This link opens in a new window

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