Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática
Ano de defesa: | 2015 |
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Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Universidade Federal de São Carlos
Câmpus São Carlos |
Programa de Pós-Graduação: |
Programa de Pós-Graduação em Química - PPGQ
|
Departamento: |
Não Informado pela instituição
|
País: |
Não Informado pela instituição
|
Palavras-chave em Português: | |
Área do conhecimento CNPq: | |
Link de acesso: | https://repositorio.ufscar.br/handle/ufscar/7718 |
Resumo: | This work reports studies of in vitro metabolism involving the compound 3-(2-chloro-6-fluorobenzyl)- imidazolidine-2,4-dione (LPSF-PT-31), a new 2-adrenoceptor agonist and, studies of enzyme phenotyping of montelukast, a drug used for the treatment of asthma. The results of this study revealed that LPSF-PT-31 is metabolized via CYP P450s in rat and human liver microsomes, producing only one major hydroxy-metabolite. LPSFPT- 31 showed a higher rate of in vitro metabolism in rats, which suggests a greater exposure to the drug in humans. The structural identification of LPSF-PT-31 metabolite’s was achieved through LC-MSn and 1H-NMR analysis that provided data to conclude that the hydroxylation occurred in the 5th position of the imidazolidine ring yielding to the production of 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4- dione. Related to the studies of enzyme phenotyping of montelukast, it was observed that the glucuronidation is the main clearance pathway of montelukast accounting for ~85% of the total apparent in vitro Clint (CYPs +UGTs) and that the CYP-mediated oxidation accounts only for ~15% to the overall metabolism of the drug, being montelukast acyl-β-D-glucuronide and montelukast 1,2 diol the major metabolites formed via UGTs and CYPs, respectively. Kinetic studies, correlation analysis, inhibition studies and, experiments in expressed CYPs and UGTs revealed that the CYP2C9 and CYP2C8 are comparably involved in the formation of montelukast 1,2- diol. CYP3A4 was responsible for the formation of 21(R)-OH montelukast and 21(S)- OH montelukast, while multiple CYPs catalyzed the formation of 25-OH montelukast (CYP2C8>2C9>3A4>2C19). The direct glucuronidation of montelukast resulted in the formation of montelukast acyl-β-D-glucuronide and of a new metabolite (Mglucuronide) not reported previously and was exclusively catalyzed by isoform UGT1A3. In conclusion, the in vitro data suggest that the applicability of montelukast as a probe of CYP2C8 activity in vitro and in vivo may be severely compromised due to important role of UGT1A3 and involvement of multiple CYPs in its metabolism. In addition, considering the lack of selective markers for UGT1A3, montelukast may be used as a selective marker of the UGT1A3 in vitro and in vivo. |
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Cardoso, Josiane de OliveiraOliveira, Regina Vincenzihttp://lattes.cnpq.br/6609377714413073Venâncio, Tiagohttp://lattes.cnpq.br/4438399441102990http://lattes.cnpq.br/77261907765960027c8e578e-284c-4891-a1d7-863fd1146bd82016-10-10T14:07:49Z2016-10-10T14:07:49Z2015-08-25CARDOSO, Josiane de Oliveira. Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática. 2015. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2015. Disponível em: https://repositorio.ufscar.br/handle/ufscar/7718.https://repositorio.ufscar.br/handle/ufscar/7718This work reports studies of in vitro metabolism involving the compound 3-(2-chloro-6-fluorobenzyl)- imidazolidine-2,4-dione (LPSF-PT-31), a new 2-adrenoceptor agonist and, studies of enzyme phenotyping of montelukast, a drug used for the treatment of asthma. The results of this study revealed that LPSF-PT-31 is metabolized via CYP P450s in rat and human liver microsomes, producing only one major hydroxy-metabolite. LPSFPT- 31 showed a higher rate of in vitro metabolism in rats, which suggests a greater exposure to the drug in humans. The structural identification of LPSF-PT-31 metabolite’s was achieved through LC-MSn and 1H-NMR analysis that provided data to conclude that the hydroxylation occurred in the 5th position of the imidazolidine ring yielding to the production of 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4- dione. Related to the studies of enzyme phenotyping of montelukast, it was observed that the glucuronidation is the main clearance pathway of montelukast accounting for ~85% of the total apparent in vitro Clint (CYPs +UGTs) and that the CYP-mediated oxidation accounts only for ~15% to the overall metabolism of the drug, being montelukast acyl-β-D-glucuronide and montelukast 1,2 diol the major metabolites formed via UGTs and CYPs, respectively. Kinetic studies, correlation analysis, inhibition studies and, experiments in expressed CYPs and UGTs revealed that the CYP2C9 and CYP2C8 are comparably involved in the formation of montelukast 1,2- diol. CYP3A4 was responsible for the formation of 21(R)-OH montelukast and 21(S)- OH montelukast, while multiple CYPs catalyzed the formation of 25-OH montelukast (CYP2C8>2C9>3A4>2C19). The direct glucuronidation of montelukast resulted in the formation of montelukast acyl-β-D-glucuronide and of a new metabolite (Mglucuronide) not reported previously and was exclusively catalyzed by isoform UGT1A3. In conclusion, the in vitro data suggest that the applicability of montelukast as a probe of CYP2C8 activity in vitro and in vivo may be severely compromised due to important role of UGT1A3 and involvement of multiple CYPs in its metabolism. In addition, considering the lack of selective markers for UGT1A3, montelukast may be used as a selective marker of the UGT1A3 in vitro and in vivo.Este trabalho relata estudos de metabolismo in vitro envolvendo o composto 3-(2-cloro-6- fluorobenzil)-imidazolidina-2,4-diona (LPSF-PT-31), um novo agonista adrenérgico 2A, e estudos de fenotipagem enzimática do montelucaste, fármaco utilizado no tratamento da asma. Os resultados do presente estudo revelaram que LPSF-PT-31 é metabolizado via CYP P450s em microssomas de fígado de ratos e humanos, produzindo apenas um hidroxi-metabólito principal. LPSF-PT-31 apresentou uma maior taxa de metabolismo in vitro em ratos, o que sugere uma maior exposição ao fármaco em seres humanos. A identificação estrutural do metabólito do LPSF-PT-31 foi estabelecida através de análises por LC-MSn e 1H-RMN, o que indicou que a reação de hidroxilação ocorreu na posição 5 do anel da imidazolidina levando a produção do metabólito 3-(2-cloro-6-fluorobenzil)-5-hidroxi-imidazolidina-2,4-diona. Em relação aos estudos de fenotipagem enzimática do montelucaste foi observado que a glucuronidação é o principal mecanismo de eliminação deste fármaco, representando ~85% do Clint in vitro aparente total (CYPs +UGTs) e que a oxidação via CYPs representa somente ~15% do Clint in vitro, sendo os metabólitos majoritários formados via UGTs e CYPs o montelucaste acil-β-D-glucuronídeo e o montelucaste 1,2 diol, respectivamente. Estudos cinéticos, de correlação com a atividade enzimática, de inibição e empregando CYPs e UGTs expressas indicaram que as CYP2C9 e CYP2C8 estão comparavelmente envolvidas na formação do montelucaste 1,2 diol. A CYP3A4 foi responsável pela formação dos metabólitos 21(R)-OH montelucaste e 21(S)-OH montelucaste, enquanto múltiplas CYPs catalisam a formação do 25-OH montelucaste (CYP2C8>2C9>3A4>2C19). A glucuronidação direta do montelucaste resultou na formação do montelucaste acil-β- D-glucuronídeo e de um novo metabólito (M-glucuronídeo) não reportado previamente e foi catalisada exclusivamente pela isoforma UGT1A3. Deste modo, os dados in vitro sugerem que a aplicabilidade do montelucaste como marcador da CYP2C8 in vitro e in vivo pode ser severamente comprometida devido ao importante papel da UGT1A3 e o envolvimento de múltiplas CYPs no seu metabolismo. Ainda, considerando a falta de marcadores seletivos para a UGT1A3, montelucaste pode ser utilizado como um marcador seletivo da UGT1A3 in vivo e in vitro.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)porUniversidade Federal de São CarlosCâmpus São CarlosPrograma de Pós-Graduação em Química - PPGQUFSCarMetabolismo in vitroIdentificação estruturalLC-MSRMNFenotipagem enzimáticaCIENCIAS EXATAS E DA TERRA::QUIMICAIdentificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimáticaStructural identification of metabolites from in vitro metabolism of bioactive compounds and studies of enzymatic phenotypinginfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisOnline600600c952ec5c-f2b5-49c6-8523-21d001220087info:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFSCARinstname:Universidade Federal de São Carlos (UFSCAR)instacron:UFSCARORIGINALTeseJOC.pdfTeseJOC.pdfapplication/pdf3485823https://repositorio.ufscar.br/bitstream/ufscar/7718/1/TeseJOC.pdf6f1dbfbe709a908e9ec5667584683225MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81957https://repositorio.ufscar.br/bitstream/ufscar/7718/2/license.txtae0398b6f8b235e40ad82cba6c50031dMD52TEXTTeseJOC.pdf.txtTeseJOC.pdf.txtExtracted texttext/plain287071https://repositorio.ufscar.br/bitstream/ufscar/7718/3/TeseJOC.pdf.txt39dada4828f41b8d2bcea87d38cf2eccMD53THUMBNAILTeseJOC.pdf.jpgTeseJOC.pdf.jpgIM Thumbnailimage/jpeg10174https://repositorio.ufscar.br/bitstream/ufscar/7718/4/TeseJOC.pdf.jpg2c6541e56c39f0462b2d5f83a7ff55a6MD54ufscar/77182023-09-18 18:30:54.022oai:repositorio.ufscar.br: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Repositório InstitucionalPUBhttps://repositorio.ufscar.br/oai/requestopendoar:43222023-09-18T18:30:54Repositório Institucional da UFSCAR - Universidade Federal de São Carlos (UFSCAR)false |
dc.title.por.fl_str_mv |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
dc.title.alternative.eng.fl_str_mv |
Structural identification of metabolites from in vitro metabolism of bioactive compounds and studies of enzymatic phenotyping |
title |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
spellingShingle |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática Cardoso, Josiane de Oliveira Metabolismo in vitro Identificação estrutural LC-MS RMN Fenotipagem enzimática CIENCIAS EXATAS E DA TERRA::QUIMICA |
title_short |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
title_full |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
title_fullStr |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
title_full_unstemmed |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
title_sort |
Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática |
author |
Cardoso, Josiane de Oliveira |
author_facet |
Cardoso, Josiane de Oliveira |
author_role |
author |
dc.contributor.authorlattes.por.fl_str_mv |
http://lattes.cnpq.br/7726190776596002 |
dc.contributor.author.fl_str_mv |
Cardoso, Josiane de Oliveira |
dc.contributor.advisor1.fl_str_mv |
Oliveira, Regina Vincenzi |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/6609377714413073 |
dc.contributor.advisor-co1.fl_str_mv |
Venâncio, Tiago |
dc.contributor.advisor-co1Lattes.fl_str_mv |
http://lattes.cnpq.br/4438399441102990 |
dc.contributor.authorID.fl_str_mv |
7c8e578e-284c-4891-a1d7-863fd1146bd8 |
contributor_str_mv |
Oliveira, Regina Vincenzi Venâncio, Tiago |
dc.subject.por.fl_str_mv |
Metabolismo in vitro Identificação estrutural LC-MS RMN Fenotipagem enzimática |
topic |
Metabolismo in vitro Identificação estrutural LC-MS RMN Fenotipagem enzimática CIENCIAS EXATAS E DA TERRA::QUIMICA |
dc.subject.cnpq.fl_str_mv |
CIENCIAS EXATAS E DA TERRA::QUIMICA |
description |
This work reports studies of in vitro metabolism involving the compound 3-(2-chloro-6-fluorobenzyl)- imidazolidine-2,4-dione (LPSF-PT-31), a new 2-adrenoceptor agonist and, studies of enzyme phenotyping of montelukast, a drug used for the treatment of asthma. The results of this study revealed that LPSF-PT-31 is metabolized via CYP P450s in rat and human liver microsomes, producing only one major hydroxy-metabolite. LPSFPT- 31 showed a higher rate of in vitro metabolism in rats, which suggests a greater exposure to the drug in humans. The structural identification of LPSF-PT-31 metabolite’s was achieved through LC-MSn and 1H-NMR analysis that provided data to conclude that the hydroxylation occurred in the 5th position of the imidazolidine ring yielding to the production of 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4- dione. Related to the studies of enzyme phenotyping of montelukast, it was observed that the glucuronidation is the main clearance pathway of montelukast accounting for ~85% of the total apparent in vitro Clint (CYPs +UGTs) and that the CYP-mediated oxidation accounts only for ~15% to the overall metabolism of the drug, being montelukast acyl-β-D-glucuronide and montelukast 1,2 diol the major metabolites formed via UGTs and CYPs, respectively. Kinetic studies, correlation analysis, inhibition studies and, experiments in expressed CYPs and UGTs revealed that the CYP2C9 and CYP2C8 are comparably involved in the formation of montelukast 1,2- diol. CYP3A4 was responsible for the formation of 21(R)-OH montelukast and 21(S)- OH montelukast, while multiple CYPs catalyzed the formation of 25-OH montelukast (CYP2C8>2C9>3A4>2C19). The direct glucuronidation of montelukast resulted in the formation of montelukast acyl-β-D-glucuronide and of a new metabolite (Mglucuronide) not reported previously and was exclusively catalyzed by isoform UGT1A3. In conclusion, the in vitro data suggest that the applicability of montelukast as a probe of CYP2C8 activity in vitro and in vivo may be severely compromised due to important role of UGT1A3 and involvement of multiple CYPs in its metabolism. In addition, considering the lack of selective markers for UGT1A3, montelukast may be used as a selective marker of the UGT1A3 in vitro and in vivo. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-08-25 |
dc.date.accessioned.fl_str_mv |
2016-10-10T14:07:49Z |
dc.date.available.fl_str_mv |
2016-10-10T14:07:49Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
format |
doctoralThesis |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
CARDOSO, Josiane de Oliveira. Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática. 2015. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2015. Disponível em: https://repositorio.ufscar.br/handle/ufscar/7718. |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufscar.br/handle/ufscar/7718 |
identifier_str_mv |
CARDOSO, Josiane de Oliveira. Identificação estrutural de metabólitos provenientes do metabolismo in vitro de compostos bioativos e estudos de fenotipagem enzimática. 2015. Tese (Doutorado em Química) – Universidade Federal de São Carlos, São Carlos, 2015. Disponível em: https://repositorio.ufscar.br/handle/ufscar/7718. |
url |
https://repositorio.ufscar.br/handle/ufscar/7718 |
dc.language.iso.fl_str_mv |
por |
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por |
dc.relation.confidence.fl_str_mv |
600 600 |
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c952ec5c-f2b5-49c6-8523-21d001220087 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.publisher.program.fl_str_mv |
Programa de Pós-Graduação em Química - PPGQ |
dc.publisher.initials.fl_str_mv |
UFSCar |
publisher.none.fl_str_mv |
Universidade Federal de São Carlos Câmpus São Carlos |
dc.source.none.fl_str_mv |
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