Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Tipo de documento: | Tese |
Idioma: | eng |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da USP |
Texto Completo: | https://www.teses.usp.br/teses/disponiveis/25/25149/tde-26012023-160317/ |
Resumo: | Individual responses to non-steroidal anti-inflammatory drugs (NSAIDs) are influenced by a combination of pharmacokinetic and pharmacodynamic factors (PK/PD) that may be under the regulatory influence of some genetic factors, which is the path for personalizing the prescription today, with satisfactory efficacy and minimal side effects. Polymorphisms in CYP2C9 can significantly interfere with the PK and PD parameters of non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen. The synthesis of prostaglandin E2 (PGE2) is modulated by the enzyme cyclooxygenase-2 (COX-2) and changes in PGE2 can be used to quantify the inhibition of COX-2 after the administration of NSAIDs, which is a good target for investigation. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a fast, selective and sensitive method of liquid chromatography coupled to mass spectrometry (LC-MS/MS) was developed and validated, according to ANVISA standards, for the determination of naproxen, its main metabolite, 6- O-desmethylnaproxen and PGE2 in saliva. Saliva collections (4 mL) were sequential in times: before and 0.25; 0.5; 0.75; 1; 1.5; two; 3; 4; 5; 6; 8; 11; 24; 48; 72 and 96 h after taking a naproxen tablet (500 mg). The PGE2 analysis proved to be effective and sensitive for the analysis of PD parameters. Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in saliva can be effectively quantified using LC-MS/MS following an oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen, its metabolite, 6-O-desmethylnaproxen, and PGE2 in saliva (2.4 ng/mL). All validation data, such as accuracy, precision, and intra- and inter-assay repeatability, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the pharmacokinetics of naproxen, its main metabolite, 6-0-desmethylnaproxen and PGE2. |
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Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MSInfluência de polimorfismos genéticos do CYP2C9 no estudo PK/PD do naproxeno em amostras de saliva por LC MS/MSCYP2C9CYP2C9Espectrometria de massasFarmacogenéticaMass spectrometryNaproxenNaproxenoPharmacogeneticsProstagladina E2Prostaglandin E2Individual responses to non-steroidal anti-inflammatory drugs (NSAIDs) are influenced by a combination of pharmacokinetic and pharmacodynamic factors (PK/PD) that may be under the regulatory influence of some genetic factors, which is the path for personalizing the prescription today, with satisfactory efficacy and minimal side effects. Polymorphisms in CYP2C9 can significantly interfere with the PK and PD parameters of non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen. The synthesis of prostaglandin E2 (PGE2) is modulated by the enzyme cyclooxygenase-2 (COX-2) and changes in PGE2 can be used to quantify the inhibition of COX-2 after the administration of NSAIDs, which is a good target for investigation. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a fast, selective and sensitive method of liquid chromatography coupled to mass spectrometry (LC-MS/MS) was developed and validated, according to ANVISA standards, for the determination of naproxen, its main metabolite, 6- O-desmethylnaproxen and PGE2 in saliva. Saliva collections (4 mL) were sequential in times: before and 0.25; 0.5; 0.75; 1; 1.5; two; 3; 4; 5; 6; 8; 11; 24; 48; 72 and 96 h after taking a naproxen tablet (500 mg). The PGE2 analysis proved to be effective and sensitive for the analysis of PD parameters. Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in saliva can be effectively quantified using LC-MS/MS following an oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen, its metabolite, 6-O-desmethylnaproxen, and PGE2 in saliva (2.4 ng/mL). All validation data, such as accuracy, precision, and intra- and inter-assay repeatability, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the pharmacokinetics of naproxen, its main metabolite, 6-0-desmethylnaproxen and PGE2.As respostas individuais aos anti-inflamatórios não esteroidais (AINES) são influenciadas por uma combinação de fatores farmacocinéticos e farmacodinâmicos (PK/PD) que podem sofrer uma influência regulatória de alguns fatores genéticos, sendo este o caminho para a personalização da prescrição atualmente, com uma eficácia satisfatória e efeitos colaterais mínimos. Os polimorfismos no CYP2C9 podem interferir significativamente nos parâmetros PK e PD dos anti-inflamatórios não esteroides (AINEs), incluindo o naproxeno. A síntese de prostaglandina E2 (PGE2) é modulada pela enzima ciclooxigenase-2 (COX-2) e mudanças na PGE2 podem ser usadas para quantificar a inibição da COX-2 após a administração dos AINES, sendo este um bom alvo de investigação. A presente pesquisa teve como objetivo estudar os parâmetros PK/PD do naproxeno e seu metabólito, 6-O-desmetilnaproxeno, associados a variações alélicas do CYP2C9. Em nosso estudo, um método rápido, seletivo e sensível de cromatografia líquida acoplada a espectrometria de massa (LC-MS/MS) foi desenvolvido e validado, de acordo com normas da ANVISA, para a determinação do naproxeno, seu principal metabólito, 6-O-desmetilnaproxeno e PGE2 em saliva. As coletas de saliva (4 mL) foram sequenciais nos tempos: antes e 0,25; 0,5; 0,75; 1; 1,5; 2; 3; 4; 5; 6; 8; 11; 24; 48; 72 e 96 h após a ingestão de um comprimido de naproxeno (500 mg). A análise da PGE2 mostrou-se eficaz e sensível para análise dos parâmetros da PD. Tanto o naproxeno quanto seu principal metabólito, 6-O-desmetilnaproxeno, e PGE2 na saliva podem ser efetivamente quantificados usando LC-MS/MS após uma dose oral de naproxeno. Nosso método mostrou-se eficaz e sensível para determinar o limite inferior de quantificação de naproxeno, seu metabólito, 6-O-desmetilnaproxeno, e PGE2 em saliva (2,4 ng/mL). Todos os dados de validação, como acurácia, precisão e repetibilidade intra e interensaio, foram inferiores a 15%. Variações alélicas do CYP2C9 podem ser consideradas relevantes na farmacocinética do naproxeno, seu principal metabólito, 6-0-desmetilnaproxeno e PGE2.Biblioteca Digitais de Teses e Dissertações da USPCalvo, Adriana MariaOliveira, Gabriela de Moraes2022-11-29info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisapplication/pdfhttps://www.teses.usp.br/teses/disponiveis/25/25149/tde-26012023-160317/reponame:Biblioteca Digital de Teses e Dissertações da USPinstname:Universidade de São Paulo (USP)instacron:USPReter o conteúdo por motivos de patente, publicação e/ou direitos autoriais.info:eu-repo/semantics/openAccesseng2024-08-02T13:30:02Zoai:teses.usp.br:tde-26012023-160317Biblioteca Digital de Teses e Dissertaçõeshttp://www.teses.usp.br/PUBhttp://www.teses.usp.br/cgi-bin/mtd2br.plvirginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.bropendoar:27212024-08-02T13:30:02Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP)false |
dc.title.none.fl_str_mv |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS Influência de polimorfismos genéticos do CYP2C9 no estudo PK/PD do naproxeno em amostras de saliva por LC MS/MS |
title |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS |
spellingShingle |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS Oliveira, Gabriela de Moraes CYP2C9 CYP2C9 Espectrometria de massas Farmacogenética Mass spectrometry Naproxen Naproxeno Pharmacogenetics Prostagladina E2 Prostaglandin E2 |
title_short |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS |
title_full |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS |
title_fullStr |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS |
title_full_unstemmed |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS |
title_sort |
Influence of CYP2C9 genetic polymorphisms in the PK/PD study of naproxen in saliva samples by LC MS/MS |
author |
Oliveira, Gabriela de Moraes |
author_facet |
Oliveira, Gabriela de Moraes |
author_role |
author |
dc.contributor.none.fl_str_mv |
Calvo, Adriana Maria |
dc.contributor.author.fl_str_mv |
Oliveira, Gabriela de Moraes |
dc.subject.por.fl_str_mv |
CYP2C9 CYP2C9 Espectrometria de massas Farmacogenética Mass spectrometry Naproxen Naproxeno Pharmacogenetics Prostagladina E2 Prostaglandin E2 |
topic |
CYP2C9 CYP2C9 Espectrometria de massas Farmacogenética Mass spectrometry Naproxen Naproxeno Pharmacogenetics Prostagladina E2 Prostaglandin E2 |
description |
Individual responses to non-steroidal anti-inflammatory drugs (NSAIDs) are influenced by a combination of pharmacokinetic and pharmacodynamic factors (PK/PD) that may be under the regulatory influence of some genetic factors, which is the path for personalizing the prescription today, with satisfactory efficacy and minimal side effects. Polymorphisms in CYP2C9 can significantly interfere with the PK and PD parameters of non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen. The synthesis of prostaglandin E2 (PGE2) is modulated by the enzyme cyclooxygenase-2 (COX-2) and changes in PGE2 can be used to quantify the inhibition of COX-2 after the administration of NSAIDs, which is a good target for investigation. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a fast, selective and sensitive method of liquid chromatography coupled to mass spectrometry (LC-MS/MS) was developed and validated, according to ANVISA standards, for the determination of naproxen, its main metabolite, 6- O-desmethylnaproxen and PGE2 in saliva. Saliva collections (4 mL) were sequential in times: before and 0.25; 0.5; 0.75; 1; 1.5; two; 3; 4; 5; 6; 8; 11; 24; 48; 72 and 96 h after taking a naproxen tablet (500 mg). The PGE2 analysis proved to be effective and sensitive for the analysis of PD parameters. Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in saliva can be effectively quantified using LC-MS/MS following an oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen, its metabolite, 6-O-desmethylnaproxen, and PGE2 in saliva (2.4 ng/mL). All validation data, such as accuracy, precision, and intra- and inter-assay repeatability, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the pharmacokinetics of naproxen, its main metabolite, 6-0-desmethylnaproxen and PGE2. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11-29 |
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.uri.fl_str_mv |
https://www.teses.usp.br/teses/disponiveis/25/25149/tde-26012023-160317/ |
url |
https://www.teses.usp.br/teses/disponiveis/25/25149/tde-26012023-160317/ |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
|
dc.rights.driver.fl_str_mv |
Reter o conteúdo por motivos de patente, publicação e/ou direitos autoriais. info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Reter o conteúdo por motivos de patente, publicação e/ou direitos autoriais. |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.coverage.none.fl_str_mv |
|
dc.publisher.none.fl_str_mv |
Biblioteca Digitais de Teses e Dissertações da USP |
publisher.none.fl_str_mv |
Biblioteca Digitais de Teses e Dissertações da USP |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da USP instname:Universidade de São Paulo (USP) instacron:USP |
instname_str |
Universidade de São Paulo (USP) |
instacron_str |
USP |
institution |
USP |
reponame_str |
Biblioteca Digital de Teses e Dissertações da USP |
collection |
Biblioteca Digital de Teses e Dissertações da USP |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da USP - Universidade de São Paulo (USP) |
repository.mail.fl_str_mv |
virginia@if.usp.br|| atendimento@aguia.usp.br||virginia@if.usp.br |
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1809091085117423616 |