In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes

[Display omitted] . ► We examined in vitro bioactivation of bazedoxifene and N-dealkylated fragment of bazedoxifene in HLM and with P450 isozymes. ► Bazedoxifene was not bioactivated under either conditions. ► An improved safety profile of bazedoxifene to available SERMs was discussed. Bazedoxifene...

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Veröffentlicht in:Chemico-biological interactions 2012-04, Vol.197 (1), p.8-15
Hauptverfasser: Lušin, Tina Trdan, Tomašić, Tihomir, Trontelj, Jurij, Mrhar, Aleš, Peterlin-Mašič, Lucija
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container_title Chemico-biological interactions
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creator Lušin, Tina Trdan
Tomašić, Tihomir
Trontelj, Jurij
Mrhar, Aleš
Peterlin-Mašič, Lucija
description [Display omitted] . ► We examined in vitro bioactivation of bazedoxifene and N-dealkylated fragment of bazedoxifene in HLM and with P450 isozymes. ► Bazedoxifene was not bioactivated under either conditions. ► An improved safety profile of bazedoxifene to available SERMs was discussed. 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.
doi_str_mv 10.1016/j.cbi.2012.03.001
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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. 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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.</description><subject>Bazedoxifene</subject><subject>cytochrome P-450</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Cytochrome P450</subject><subject>drugs</subject><subject>estrogen receptors</subject><subject>glutathione</subject><subject>Glutathione - metabolism</subject><subject>Humans</subject><subject>Indoles - chemistry</subject><subject>Indoles - metabolism</subject><subject>Isoenzymes - metabolism</subject><subject>isozymes</subject><subject>LC–MS/MS</subject><subject>liver microsomes</subject><subject>metabolites</subject><subject>Microsomes, Liver - metabolism</subject><subject>osteoporosis</subject><subject>postmenopause</subject><subject>Raloxifene</subject><subject>Raloxifene Hydrochloride - chemistry</subject><subject>Raloxifene Hydrochloride - metabolism</subject><subject>Reactive metabolite</subject><subject>Selective Estrogen Receptor Modulators - chemistry</subject><subject>Selective Estrogen Receptor Modulators - metabolism</subject><subject>Tandem Mass Spectrometry</subject><subject>toxicity</subject><issn>0009-2797</issn><issn>1872-7786</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EokvhAbiAj-XgYDtO7IhTVQGtVIkD9Gw59pj1KrEXO7tqeHq82sKR02ik7_81-gaht4w2jLL-466xY2g4ZbyhbUMpe4Y2TElOpFT9c7ShlA6Ey0FeoFel7OpKuaAv0QXngg-i5xuU7iI-hiUnPIZk7BKOZgkp4uTxaH6DS4_BQwRsosOcXAmyXV1Oj-t-C3GdPpCWzLBs14mwWxKiSxPpSJpwiHh7mE3EUzhCxnOwOZU0Q3mNXngzFXjzNC_Rw5fPP25uyf23r3c31_fEtlIupGtHypQF2XOwVnSmN5zxTjnqxdAPUnnbeWWkGz0dqWQjFaJlApwcVdtb316iq3PvPqdfByiLnkOxME0mQjoUzaoaxqUcVEXZGT3dWDJ4vc9hNnmtkD551jtdPeuTZ01bXT3XzLun-sM4g_uX-Cu2Au_PgDdJm585FP3wvTZ09Qe96rioxKczAVXDMUDWxQaIFlzIYBftUvjPAX8A946WWQ</recordid><startdate>20120415</startdate><enddate>20120415</enddate><creator>Lušin, Tina Trdan</creator><creator>Tomašić, Tihomir</creator><creator>Trontelj, Jurij</creator><creator>Mrhar, Aleš</creator><creator>Peterlin-Mašič, Lucija</creator><general>Elsevier Ireland Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120415</creationdate><title>In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes</title><author>Lušin, Tina Trdan ; Tomašić, Tihomir ; Trontelj, Jurij ; Mrhar, Aleš ; Peterlin-Mašič, Lucija</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c377t-53b018ce762ecc45a6a21258d0f496978fc5f8a7dbf0b071b044314ed7b836cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Bazedoxifene</topic><topic>cytochrome P-450</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Cytochrome P450</topic><topic>drugs</topic><topic>estrogen receptors</topic><topic>glutathione</topic><topic>Glutathione - metabolism</topic><topic>Humans</topic><topic>Indoles - chemistry</topic><topic>Indoles - metabolism</topic><topic>Isoenzymes - metabolism</topic><topic>isozymes</topic><topic>LC–MS/MS</topic><topic>liver microsomes</topic><topic>metabolites</topic><topic>Microsomes, Liver - metabolism</topic><topic>osteoporosis</topic><topic>postmenopause</topic><topic>Raloxifene</topic><topic>Raloxifene Hydrochloride - chemistry</topic><topic>Raloxifene Hydrochloride - metabolism</topic><topic>Reactive metabolite</topic><topic>Selective Estrogen Receptor Modulators - chemistry</topic><topic>Selective Estrogen Receptor Modulators - metabolism</topic><topic>Tandem Mass Spectrometry</topic><topic>toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lušin, Tina Trdan</creatorcontrib><creatorcontrib>Tomašić, Tihomir</creatorcontrib><creatorcontrib>Trontelj, Jurij</creatorcontrib><creatorcontrib>Mrhar, Aleš</creatorcontrib><creatorcontrib>Peterlin-Mašič, Lucija</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Chemico-biological interactions</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lušin, Tina Trdan</au><au>Tomašić, Tihomir</au><au>Trontelj, Jurij</au><au>Mrhar, Aleš</au><au>Peterlin-Mašič, Lucija</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes</atitle><jtitle>Chemico-biological interactions</jtitle><addtitle>Chem Biol Interact</addtitle><date>2012-04-15</date><risdate>2012</risdate><volume>197</volume><issue>1</issue><spage>8</spage><epage>15</epage><pages>8-15</pages><issn>0009-2797</issn><eissn>1872-7786</eissn><abstract>[Display omitted] . ► We examined in vitro bioactivation of bazedoxifene and N-dealkylated fragment of bazedoxifene in HLM and with P450 isozymes. ► Bazedoxifene was not bioactivated under either conditions. ► An improved safety profile of bazedoxifene to available SERMs was discussed. 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.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>22429462</pmid><doi>10.1016/j.cbi.2012.03.001</doi><tpages>8</tpages></addata></record>
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ispartof Chemico-biological interactions, 2012-04, Vol.197 (1), p.8-15
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subjects Bazedoxifene
cytochrome P-450
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
drugs
estrogen receptors
glutathione
Glutathione - metabolism
Humans
Indoles - chemistry
Indoles - metabolism
Isoenzymes - metabolism
isozymes
LC–MS/MS
liver microsomes
metabolites
Microsomes, Liver - metabolism
osteoporosis
postmenopause
Raloxifene
Raloxifene Hydrochloride - chemistry
Raloxifene Hydrochloride - metabolism
Reactive metabolite
Selective Estrogen Receptor Modulators - chemistry
Selective Estrogen Receptor Modulators - metabolism
Tandem Mass Spectrometry
toxicity
title In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol in human liver microsomes
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