title: In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes.
abstract: 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 (HLMs) 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.
authors.affiliation: University of Ljubljana, Aškerčeva, Ljubljana, Slovenia.
authors.forename: Tina Trdan
authors.initials: TT
authors.lastname: Lušin
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašić
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.forename: Aleš
authors.initials: A
authors.lastname: Mrhar
authors.forename: Lucija
authors.initials: L
authors.lastname: Peterlin-Mašič
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism*; D020849:Raloxifene Hydrochloride / Q000737:chemistry / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D007211:Indoles; D007527:Isoenzymes; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; C447119:bazedoxifene