Disposition of eslicarbazepine acetate in the mouse after oral administration
Autor(a) principal: | |
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Data de Publicação: | 2008 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/101121 https://doi.org/10.1111/j.1472-8206.2008.00617.x |
Resumo: | Eslicarbazepine acetate is a promising antiepileptic drug structurally related to carbamazepine and oxcarbazepine, which is in the final phase of clinical development. The metabolism of eslicarbazepine acetate is clearly species dependent and, in this case, among small laboratory animals, the mouse seems to be the most relevant species to humans. Hence, the aim of this study was to investigate the plasma, brain and liver disposition of eslicarbazepine acetate in mice to better understand its disposition in humans. Adult male CD-1 mice were treated orally with a single dose of eslicarbazepine acetate 350 mg/kg. Blood samples, brain and liver tissues were taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 10, 16 and 24 h post-dose. Plasma and tissue levels of eslicarbazepine acetate and its metabolites (S-licarbazepine, R-licarbazepine and oxcarbazepine) were assessed by using high-performance liquid chromatographyultraviolet detection. Both eslicarbazepine acetate and R-licarbazepine concentrations were below the limit of quantification of the assay in all matrices. Eslicarbazepine acetate was rapidly and extensively metabolized to S-licarbazepine (major metabolite), which was oxidized to oxcarbazepine to a small extent. The brain/plasma ratios suggest that the brain exposure to S-licarbazepine and oxcarbazepine was approximately 30% of their total systemic exposure. However, S-licarbazepine crossed the blood–brain barrier (BBB) less efficiently than oxcarbazepine. On the other hand, the liver/plasma ratios support the notion that S-licarbazepine undergoes hepatic accumulation, whereas oxcarbazepine appears to leave this compartment twice as fast as S-licarbazepine. Thus, the diffusion through the BBB is favourable to oxcarbazepine and the liver acts like a deposit of the pharmacologically active metabolite of eslicarbazepine acetate (S-licarbazepine). |
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Disposition of eslicarbazepine acetate in the mouse after oral administrationeslicarbazepine acetatemetabolismmouseoxcarbazepinetissue dispositionEslicarbazepine acetate is a promising antiepileptic drug structurally related to carbamazepine and oxcarbazepine, which is in the final phase of clinical development. The metabolism of eslicarbazepine acetate is clearly species dependent and, in this case, among small laboratory animals, the mouse seems to be the most relevant species to humans. Hence, the aim of this study was to investigate the plasma, brain and liver disposition of eslicarbazepine acetate in mice to better understand its disposition in humans. Adult male CD-1 mice were treated orally with a single dose of eslicarbazepine acetate 350 mg/kg. Blood samples, brain and liver tissues were taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 10, 16 and 24 h post-dose. Plasma and tissue levels of eslicarbazepine acetate and its metabolites (S-licarbazepine, R-licarbazepine and oxcarbazepine) were assessed by using high-performance liquid chromatographyultraviolet detection. Both eslicarbazepine acetate and R-licarbazepine concentrations were below the limit of quantification of the assay in all matrices. Eslicarbazepine acetate was rapidly and extensively metabolized to S-licarbazepine (major metabolite), which was oxidized to oxcarbazepine to a small extent. The brain/plasma ratios suggest that the brain exposure to S-licarbazepine and oxcarbazepine was approximately 30% of their total systemic exposure. However, S-licarbazepine crossed the blood–brain barrier (BBB) less efficiently than oxcarbazepine. On the other hand, the liver/plasma ratios support the notion that S-licarbazepine undergoes hepatic accumulation, whereas oxcarbazepine appears to leave this compartment twice as fast as S-licarbazepine. Thus, the diffusion through the BBB is favourable to oxcarbazepine and the liver acts like a deposit of the pharmacologically active metabolite of eslicarbazepine acetate (S-licarbazepine).3910-3178-31BA | MARIA MARGARIDA COUTINHO DE SEABRA CASTEL-BRANCO CAETANOinfo:eu-repo/semantics/publishedVersionSociété Française de Pharmacologie et de Thérapeutique2008info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/101121http://hdl.handle.net/10316/101121https://doi.org/10.1111/j.1472-8206.2008.00617.xengcv-prod-143883Alves, GilbertoFigueiredo, IsabelCastel-Branco, MargaridaLourenço, NulitaFalcão, AmílcarCaramona, MargaridaSoares-da-Silva, Patrícioinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-10-20T13:36:36Zoai:estudogeral.uc.pt:10316/101121Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:18:21.559513Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
title |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
spellingShingle |
Disposition of eslicarbazepine acetate in the mouse after oral administration Alves, Gilberto eslicarbazepine acetate metabolism mouse oxcarbazepine tissue disposition |
title_short |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
title_full |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
title_fullStr |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
title_full_unstemmed |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
title_sort |
Disposition of eslicarbazepine acetate in the mouse after oral administration |
author |
Alves, Gilberto |
author_facet |
Alves, Gilberto Figueiredo, Isabel Castel-Branco, Margarida Lourenço, Nulita Falcão, Amílcar Caramona, Margarida Soares-da-Silva, Patrício |
author_role |
author |
author2 |
Figueiredo, Isabel Castel-Branco, Margarida Lourenço, Nulita Falcão, Amílcar Caramona, Margarida Soares-da-Silva, Patrício |
author2_role |
author author author author author author |
dc.contributor.author.fl_str_mv |
Alves, Gilberto Figueiredo, Isabel Castel-Branco, Margarida Lourenço, Nulita Falcão, Amílcar Caramona, Margarida Soares-da-Silva, Patrício |
dc.subject.por.fl_str_mv |
eslicarbazepine acetate metabolism mouse oxcarbazepine tissue disposition |
topic |
eslicarbazepine acetate metabolism mouse oxcarbazepine tissue disposition |
description |
Eslicarbazepine acetate is a promising antiepileptic drug structurally related to carbamazepine and oxcarbazepine, which is in the final phase of clinical development. The metabolism of eslicarbazepine acetate is clearly species dependent and, in this case, among small laboratory animals, the mouse seems to be the most relevant species to humans. Hence, the aim of this study was to investigate the plasma, brain and liver disposition of eslicarbazepine acetate in mice to better understand its disposition in humans. Adult male CD-1 mice were treated orally with a single dose of eslicarbazepine acetate 350 mg/kg. Blood samples, brain and liver tissues were taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 10, 16 and 24 h post-dose. Plasma and tissue levels of eslicarbazepine acetate and its metabolites (S-licarbazepine, R-licarbazepine and oxcarbazepine) were assessed by using high-performance liquid chromatographyultraviolet detection. Both eslicarbazepine acetate and R-licarbazepine concentrations were below the limit of quantification of the assay in all matrices. Eslicarbazepine acetate was rapidly and extensively metabolized to S-licarbazepine (major metabolite), which was oxidized to oxcarbazepine to a small extent. The brain/plasma ratios suggest that the brain exposure to S-licarbazepine and oxcarbazepine was approximately 30% of their total systemic exposure. However, S-licarbazepine crossed the blood–brain barrier (BBB) less efficiently than oxcarbazepine. On the other hand, the liver/plasma ratios support the notion that S-licarbazepine undergoes hepatic accumulation, whereas oxcarbazepine appears to leave this compartment twice as fast as S-licarbazepine. Thus, the diffusion through the BBB is favourable to oxcarbazepine and the liver acts like a deposit of the pharmacologically active metabolite of eslicarbazepine acetate (S-licarbazepine). |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008 |
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/10316/101121 http://hdl.handle.net/10316/101121 https://doi.org/10.1111/j.1472-8206.2008.00617.x |
url |
http://hdl.handle.net/10316/101121 https://doi.org/10.1111/j.1472-8206.2008.00617.x |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
cv-prod-143883 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Société Française de Pharmacologie et de Thérapeutique |
publisher.none.fl_str_mv |
Société Française de Pharmacologie et de Thérapeutique |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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