Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry

Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Kaddah, Mohamed M.Y. [verfasserIn] Billig, Susan [verfasserIn] Oehme, Ramona [verfasserIn] Birkemeyer, Claudia [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2021

Schlagwörter:	Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity

Übergeordnetes Werk:	Enthalten in: Journal of chromatography / A - New York, NY [u.a.] : Science Direct, 1958, 1645
Übergeordnetes Werk:	volume:1645

DOI / URN:	10.1016/j.chroma.2021.462095

Katalog-ID:	ELV00590093X

Internformat


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100	1		\|a Kaddah, Mohamed M.Y. \|e verfasserin \|0 (orcid)0000-0003-0575-2458 \|4 aut
245	1	0	\|a Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
264		1	\|c 2021
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520			\|a Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity.
650		4	\|a Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF)
650		4	\|a Broadband collision induced dissociation (bbCID)
650		4	\|a Triple quadrupole mass spectrometer
650		4	\|a Simeprevir
650		4	\|a Reactive metabolites
650		4	\|a Hepatotoxicity
700	1		\|a Billig, Susan \|e verfasserin \|4 aut
700	1		\|a Oehme, Ramona \|e verfasserin \|4 aut
700	1		\|a Birkemeyer, Claudia \|e verfasserin \|4 aut
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912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4393
936	b	k	\|a 35.00 \|j Chemie: Allgemeines
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952			\|d 1645

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publishDate	2021
allfields	10.1016/j.chroma.2021.462095 doi (DE-627)ELV00590093X (ELSEVIER)S0021-9673(21)00219-3 DE-627 ger DE-627 rda eng 540 DE-600 35.00 bkl Kaddah, Mohamed M.Y. verfasserin (orcid)0000-0003-0575-2458 aut Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity. Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity Billig, Susan verfasserin aut Oehme, Ramona verfasserin aut Birkemeyer, Claudia verfasserin aut Enthalten in Journal of chromatography / A New York, NY [u.a.] : Science Direct, 1958 1645 Online-Ressource (DE-627)302467416 (DE-600)1491247-8 (DE-576)094950253 1873-3778 nnns volume:1645 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.00 Chemie: Allgemeines AR 1645
spelling	10.1016/j.chroma.2021.462095 doi (DE-627)ELV00590093X (ELSEVIER)S0021-9673(21)00219-3 DE-627 ger DE-627 rda eng 540 DE-600 35.00 bkl Kaddah, Mohamed M.Y. verfasserin (orcid)0000-0003-0575-2458 aut Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity. Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity Billig, Susan verfasserin aut Oehme, Ramona verfasserin aut Birkemeyer, Claudia verfasserin aut Enthalten in Journal of chromatography / A New York, NY [u.a.] : Science Direct, 1958 1645 Online-Ressource (DE-627)302467416 (DE-600)1491247-8 (DE-576)094950253 1873-3778 nnns volume:1645 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.00 Chemie: Allgemeines AR 1645
allfields_unstemmed	10.1016/j.chroma.2021.462095 doi (DE-627)ELV00590093X (ELSEVIER)S0021-9673(21)00219-3 DE-627 ger DE-627 rda eng 540 DE-600 35.00 bkl Kaddah, Mohamed M.Y. verfasserin (orcid)0000-0003-0575-2458 aut Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity. Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity Billig, Susan verfasserin aut Oehme, Ramona verfasserin aut Birkemeyer, Claudia verfasserin aut Enthalten in Journal of chromatography / A New York, NY [u.a.] : Science Direct, 1958 1645 Online-Ressource (DE-627)302467416 (DE-600)1491247-8 (DE-576)094950253 1873-3778 nnns volume:1645 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.00 Chemie: Allgemeines AR 1645
allfieldsGer	10.1016/j.chroma.2021.462095 doi (DE-627)ELV00590093X (ELSEVIER)S0021-9673(21)00219-3 DE-627 ger DE-627 rda eng 540 DE-600 35.00 bkl Kaddah, Mohamed M.Y. verfasserin (orcid)0000-0003-0575-2458 aut Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity. Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity Billig, Susan verfasserin aut Oehme, Ramona verfasserin aut Birkemeyer, Claudia verfasserin aut Enthalten in Journal of chromatography / A New York, NY [u.a.] : Science Direct, 1958 1645 Online-Ressource (DE-627)302467416 (DE-600)1491247-8 (DE-576)094950253 1873-3778 nnns volume:1645 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.00 Chemie: Allgemeines AR 1645
allfieldsSound	10.1016/j.chroma.2021.462095 doi (DE-627)ELV00590093X (ELSEVIER)S0021-9673(21)00219-3 DE-627 ger DE-627 rda eng 540 DE-600 35.00 bkl Kaddah, Mohamed M.Y. verfasserin (orcid)0000-0003-0575-2458 aut Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry 2021 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity. Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity Billig, Susan verfasserin aut Oehme, Ramona verfasserin aut Birkemeyer, Claudia verfasserin aut Enthalten in Journal of chromatography / A New York, NY [u.a.] : Science Direct, 1958 1645 Online-Ressource (DE-627)302467416 (DE-600)1491247-8 (DE-576)094950253 1873-3778 nnns volume:1645 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.00 Chemie: Allgemeines AR 1645
language	English
source	Enthalten in Journal of chromatography / A 1645 volume:1645
sourceStr	Enthalten in Journal of chromatography / A 1645 volume:1645
format_phy_str_mv	Article
bklname	Chemie: Allgemeines
institution	findex.gbv.de
topic_facet	Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity
dewey-raw	540
isfreeaccess_bool	false
container_title	Journal of chromatography / A
authorswithroles_txt_mv	Kaddah, Mohamed M.Y. @@aut@@ Billig, Susan @@aut@@ Oehme, Ramona @@aut@@ Birkemeyer, Claudia @@aut@@
publishDateDaySort_date	2021-01-01T00:00:00Z
hierarchy_top_id	302467416
dewey-sort	3540
id	ELV00590093X
language_de	englisch
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author	Kaddah, Mohamed M.Y.
spellingShingle	Kaddah, Mohamed M.Y. ddc 540 bkl 35.00 misc Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) misc Broadband collision induced dissociation (bbCID) misc Triple quadrupole mass spectrometer misc Simeprevir misc Reactive metabolites misc Hepatotoxicity Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
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topic_title	540 DE-600 35.00 bkl Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) Broadband collision induced dissociation (bbCID) Triple quadrupole mass spectrometer Simeprevir Reactive metabolites Hepatotoxicity
topic	ddc 540 bkl 35.00 misc Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) misc Broadband collision induced dissociation (bbCID) misc Triple quadrupole mass spectrometer misc Simeprevir misc Reactive metabolites misc Hepatotoxicity
topic_unstemmed	ddc 540 bkl 35.00 misc Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) misc Broadband collision induced dissociation (bbCID) misc Triple quadrupole mass spectrometer misc Simeprevir misc Reactive metabolites misc Hepatotoxicity
topic_browse	ddc 540 bkl 35.00 misc Ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) misc Broadband collision induced dissociation (bbCID) misc Triple quadrupole mass spectrometer misc Simeprevir misc Reactive metabolites misc Hepatotoxicity
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title	Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
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title_full	Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
author_sort	Kaddah, Mohamed M.Y.
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author_browse	Kaddah, Mohamed M.Y. Billig, Susan Oehme, Ramona Birkemeyer, Claudia
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title_sort	bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
title_auth	Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
abstract	Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity.
abstractGer	Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity.
abstract_unstemmed	Liquid chromatography coupled to a triple quadrupole and, alternatively, to an ultrahigh-resolution quadrupole time-of-flight (UHR-QqTOF) mass spectrometers was used to collect qualitative and quantitative information from incubations of the anti-hepatitis C drug simeprevir with human and rat liver microsomes, respectively, supplemented with NADPH and glutathione. For this, different chromatographic methods using two different chromatographic columns, Kinetex® 2.6 µm C18 (50 × 3 mm) and Atlantis T3 (100 Å, 3 µm, 4.6 mm × 150 mm), have been employed. For determination and structural characterization of the reactive metabolites, we used information obtained from high-resolution mass spectrometry, namely accurate mass data to calculate the elemental composition, accurate MS/MS fragmentation patterns for confirmation of structural proposals, and the high mass spectral resolution to eliminate false-positive peaks. In this study, the use of high-resolution mass spectrometry (HR-MS) enabled the identification of 19 simeprevir metabolites generated by O- respectively N-demethylation, oxidation, dehydrogenation, hydrolysis, and formation of glutathione conjugates. The in silico study provides insights into the sites of simeprevir most amenable to reactions involving cytochrome P450. The developed methods have been successfully applied to analyze simeprevir and its metabolites simultaneously; based on this data, potential metabolic pathways of simeprevir are discussed. In general, the obtained results demonstrate that simeprevir is susceptible to form reactive simeprevir-glutathione adducts and cyclopropansulfonamide, which may explain the implication of simeprevir in idiosyncratic adverse drug reactions (IADRs) or hepatotoxicity.
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title_short	Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry
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author2	Billig, Susan Oehme, Ramona Birkemeyer, Claudia
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Bio-activation of simeprevir in liver microsomes and characterization of its glutathione conjugates by liquid chromatography coupled to ultrahigh-resolution quadrupole time-of-flight mass spectrometry

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