In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes |
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| Authors: | Lušin Tina Trdan Tomašić Tihomir Trontelj Jurij Mrhar Aleš Peterlin-Mašič Lucija |
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| Institution: | 1. Department of Chemistry, National Taiwan University, Taipei 106, Taiwan;2. The Genomics Research Center, Academia Sinica, Taipei 115, Taiwan;1. Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy;2. Molecular Virology and Gene Therapy, KU Leuven and IRC KULAK, Kapucijnenvoer 33, B-3000 Leuven, Flanders, Belgium;1. CQB, Centro de Química e Bioquímica, Departamento de Química e Bioquímica da Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal;2. Departmento de Química, CICECO and Secção Autónoma de Ciências da Saúde, Universidade de Aveiro, 3810-193, Aveiro, Portugal;3. ITQB, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Apartado 127, 2780-901 Oeiras, Portugal;4. REQUIMTE, CQFB, Centro de Química Fina e Biotecnologia, Departamento de Química, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Quinta da Torre, 2825-114 Monte da Caparica, Portugal;5. CFA, Centro de Física Atómica, Departamento de Física, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Quinta da Torre, 2829-516 Caparica, Portugal;1. Sustainable Energy Laboratory, Faculty of Material Science and Chemistry, China University of Geosciences, Wuhan 430074, PR China;2. Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore;1. Cardio-Electrophysiology Research Laboratory, Medical College, Wuhan University of Science and Technology, Wuhan 430081, China;2. Department of Electrophysiology, Institute of Cardiovasology, Luzhou Medical College, Luzhou, Sichuan 646000, China |
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| 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. |
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