Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model

Detalhes bibliográficos
Autor(a) principal: Meirinho, Sara
Data de Publicação: 2023
Outros Autores: Rodrigues, Márcio, Fortuna, Ana, Falcão, Amílcar, Alves, Gilberto
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
Texto Completo: http://hdl.handle.net/10314/6261
Resumo: New-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model. To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 μM), rufinamide (100 μM) or stiripentol (5 μM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction. Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism. Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.
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spelling Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human modelDrug-drug interactionsHepaRG cellsMetabolic stabilityPerampanelRufinamideStiripentolNew-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model. To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 μM), rufinamide (100 μM) or stiripentol (5 μM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction. Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism. Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.2023-01-06T09:01:59Z2023-01-06T09:01:59Z2023-01-06info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10314/6261http://hdl.handle.net/10314/6261eng0887-2333Meirinho, SaraRodrigues, MárcioFortuna, AnaFalcão, AmílcarAlves, Gilbertoinfo:eu-repo/semantics/openAccessreponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiainstacron:RCAAP2025-01-05T03:02:37Zoai:bdigital.ipg.pt:10314/6261Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireinfo@rcaap.ptopendoar:https://opendoar.ac.uk/repository/71602025-05-28T19:26:37.951116Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologiafalse
dc.title.none.fl_str_mv Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
title Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
spellingShingle Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
Meirinho, Sara
Drug-drug interactions
HepaRG cells
Metabolic stability
Perampanel
Rufinamide
Stiripentol
title_short Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
title_full Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
title_fullStr Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
title_full_unstemmed Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
title_sort Study of the metabolic stability profiles of perampanel, rufinamide and stiripentol and prediction of drug interactions using HepaRG cells as an in vitro human model
author Meirinho, Sara
author_facet Meirinho, Sara
Rodrigues, Márcio
Fortuna, Ana
Falcão, Amílcar
Alves, Gilberto
author_role author
author2 Rodrigues, Márcio
Fortuna, Ana
Falcão, Amílcar
Alves, Gilberto
author2_role author
author
author
author
dc.contributor.author.fl_str_mv Meirinho, Sara
Rodrigues, Márcio
Fortuna, Ana
Falcão, Amílcar
Alves, Gilberto
dc.subject.por.fl_str_mv Drug-drug interactions
HepaRG cells
Metabolic stability
Perampanel
Rufinamide
Stiripentol
topic Drug-drug interactions
HepaRG cells
Metabolic stability
Perampanel
Rufinamide
Stiripentol
description New-generation antiepileptic drugs as perampanel, rufinamide and stiripentol emerged as alternatives in chronic epilepsy polytherapy. Hence, their metabolic stability and potential involvement in relevant drug-drug interactions (DDI) are of great clinical interest, being HepaRG cells herein used as an in vitro human model. To characterize their metabolic stability profiles, HepaRG cells were incubated with perampanel (1 μM), rufinamide (100 μM) or stiripentol (5 μM) for 12-h. HepaRG cells, pretreated with known CYP450 isoenzymes inducers (rifampicin, phenytoin, phenobarbital, omeprazole and carbamazepine), were also incubated with perampanel, rufinamide or stiripentol to assess possible DDI mediated by CYP450 induction. Results suggest a considerable decrease in perampanel and stiripentol concentrations over 12-h; contrary, rufinamide concentrations did not variated. Cells pretreatment with all inducers significantly decreased stiripentol concentrations (between 20.3% and 31.9%), suggesting a considerable potential for DDI. Rufinamide concentrations only decreased when preincubated with rifampicin and with the highest tested concentrations of the remaining inducers. Perampanel levels decreased with rifampicin, carbamazepine and phenobarbital, supporting the involvement of CYP3A4-mediated metabolism. Besides relevant information concerning the metabolic stability profile and potential DDIs of the new antiepileptics here studied, it was also reinforced the HepaRG cells suitability as a reliable in vitro model to foresee in vivo metabolism in humans.
publishDate 2023
dc.date.none.fl_str_mv 2023-01-06T09:01:59Z
2023-01-06T09:01:59Z
2023-01-06
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10314/6261
http://hdl.handle.net/10314/6261
url http://hdl.handle.net/10314/6261
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 0887-2333
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
instname:FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron:RCAAP
instname_str FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
instacron_str RCAAP
institution RCAAP
reponame_str Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
collection Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
repository.name.fl_str_mv Repositórios Científicos de Acesso Aberto de Portugal (RCAAP) - FCCN, serviços digitais da FCT – Fundação para a Ciência e a Tecnologia
repository.mail.fl_str_mv info@rcaap.pt
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