Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439
OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxy...
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| Veröffentlicht in: | ACS infectious diseases 2021-07, Vol.7 (7), p.1885-1893 |
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| creator | Shackleford, David M Chiu, Francis C. K Katneni, Kasiram Blundell, Scott McLaren, Jenna Wang, Xiaofang Zhou, Lin Sriraghavan, Kamaraj Alker, André M Hunziker, Daniel Scheurer, Christian Zhao, Qingjie Dong, Yuxiang Möhrle, Jörg J Abla, Nada Matile, Hugues Wittlin, Sergio Vennerstrom, Jonathan L Charman, Susan A |
| description | OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug–drug interactions and support physiologically based pharmacokinetic (PBPK) modeling. |
| doi_str_mv | 10.1021/acsinfecdis.1c00225 |
| format | Article |
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K ; Katneni, Kasiram ; Blundell, Scott ; McLaren, Jenna ; Wang, Xiaofang ; Zhou, Lin ; Sriraghavan, Kamaraj ; Alker, André M ; Hunziker, Daniel ; Scheurer, Christian ; Zhao, Qingjie ; Dong, Yuxiang ; Möhrle, Jörg J ; Abla, Nada ; Matile, Hugues ; Wittlin, Sergio ; Vennerstrom, Jonathan L ; Charman, Susan A</creator><creatorcontrib>Shackleford, David M ; Chiu, Francis C. K ; Katneni, Kasiram ; Blundell, Scott ; McLaren, Jenna ; Wang, Xiaofang ; Zhou, Lin ; Sriraghavan, Kamaraj ; Alker, André M ; Hunziker, Daniel ; Scheurer, Christian ; Zhao, Qingjie ; Dong, Yuxiang ; Möhrle, Jörg J ; Abla, Nada ; Matile, Hugues ; Wittlin, Sergio ; Vennerstrom, Jonathan L ; Charman, Susan A</creatorcontrib><description>OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug–drug interactions and support physiologically based pharmacokinetic (PBPK) modeling.</description><identifier>ISSN: 2373-8227</identifier><identifier>EISSN: 2373-8227</identifier><identifier>DOI: 10.1021/acsinfecdis.1c00225</identifier><identifier>PMID: 34101429</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antimalarials ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System ; Humans ; Microsomes, Liver ; Peroxides</subject><ispartof>ACS infectious diseases, 2021-07, Vol.7 (7), p.1885-1893</ispartof><rights>2021 The Authors. 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Dis</addtitle><description>OZ439 is a potent synthetic ozonide evaluated for the treatment of uncomplicated malaria. The metabolite profile of OZ439 was characterized in vitro using human liver microsomes combined with LC/MS-MS, chemical derivatization, and metabolite synthesis. The primary biotransformations were monohydroxylation at the three distal carbon atoms of the spiroadamantane substructure, with minor contributions from N-oxidation of the morpholine nitrogen and deethylation cleavage of the morpholine ring. Secondary transformations resulted in the formation of dihydroxylation metabolites and metabolites containing both monohydroxylation and morpholine N-oxidation. With the exception of two minor metabolites, none of the other metabolites had appreciable antimalarial activity. Reaction phenotyping indicated that CYP3A4 is the enzyme responsible for the metabolism of OZ439, and it was found to inhibit CYP3A via both direct and mechanism-based inhibition. Elucidation of the metabolic pathways and kinetics will assist with efforts to predict potential metabolic drug–drug interactions and support physiologically based pharmacokinetic (PBPK) modeling.</description><subject>Antimalarials</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System</subject><subject>Humans</subject><subject>Microsomes, Liver</subject><subject>Peroxides</subject><issn>2373-8227</issn><issn>2373-8227</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtLAzEUhYMoWmp_gSD5A2PznMdGkOILLC2oC92EvMaJTBPJpGL_vZGq1I2rc-Hec-7hA-AEozOMCJ5KPTjfWm3ccIY1QoTwPTAitKJFTUi1vzMfgckwvCKEMK05Y_wQHFGGEWakGQEz26SguxhWFi4ZR8XcGieTNXBuk1Shd8MKSm_g7GkJb33nlEsueNiGCFNn4f3GZ0lOw6WN4cMZCy98civZy-hkDxfPjDbH4KCV_WAn3zoGj1eXD7Ob4m5xfTu7uCtkrpUKUmHKVVmVijJuiOGGNpVtraSM6TxVWEnOmkaVDeNKEVVqbmpsbdlUnOqSjsH5NvdtrVbWaOtTlL14i7lP3Iggnfi78a4TL-Fd1DUiJa5zAN0G6BiGIdr214uR-OIudriLb-7Zdbr79tfzQzkfTLcH2S1ewzr6TOHfyE--1JI9</recordid><startdate>20210709</startdate><enddate>20210709</enddate><creator>Shackleford, David M</creator><creator>Chiu, Francis C. 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| subjects | Antimalarials Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System Humans Microsomes, Liver Peroxides |
| title | Cytochrome P450-Mediated Metabolism and CYP Inhibition for the Synthetic Peroxide Antimalarial OZ439 |
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