Characterization of Casearin X Metabolism by Rat and Human Liver Microsomes

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Autor(es): dc.contributorUniversidade de São Paulo (USP)-
Autor(es): dc.contributorUniversidade Do Estado de São Paulo-
Autor(es): dc.creatorMoreira Da Silva, Rodrigo-
Autor(es): dc.creatorDe Gaitani, Cristiane Masetto-
Autor(es): dc.creatorMarques, Lucas Maciel Mauriz-
Autor(es): dc.creatorFraige Baraco, Karina-
Autor(es): dc.creatorCavalheiro, Alberto José-
Autor(es): dc.creatorDe Moraes, Luiz Alberto Beraldo-
Autor(es): dc.creatorLopes, Norberto Peporine-
Autor(es): dc.creatorDe Oliveira, Anderson Rodrigo Moraes-
Data de aceite: dc.date.accessioned2025-08-21T21:29:04Z-
Data de disponibilização: dc.date.available2025-08-21T21:29:04Z-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2019-01-01-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1055/a-0765-9523-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/231429-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/231429-
Descrição: dc.descriptionCasearin X (CAS X) is the major clerodane diterpene isolated from the leaves of Casearia sylvestris and has been extensively studied due to its powerful cytotoxic activity at low concentrations. Promising results for in vivo antitumor action have also been described when CAS X was administered intraperitoneally in mice. Conversely, loss of activity was observed when orally administered. Since the advancement of natural products as drug candidates requires satisfactory bioavailability for their pharmacological effect, this work aimed to characterize the CAS X metabolism by employing an in vitro microsomal model for the prediction of preclinical pharmacokinetic data. Rat and human liver microsomes were used to assess species differences. A high-performance liquid chromatography with diode-array detection (HPLC-DAD) method for the quantification of CAS X in microsomes was developed and validated according to European Medicines Agency guidelines. CAS X was demonstrated to be a substrate for carboxylesterases via hydrolysis reaction, with a Michaelis-Menten kinetic profile. The enzyme kinetic parameters were determined, and the intrinsic clearance was 1.7-fold higher in humans than in rats. The hepatic clearance was estimated by in vitro - in vivo extrapolation, resulting in more than 90% of the hepatic blood flow for both species. A qualitative study was also carried out for the metabolite identification by mass spectrometry and indicated the formation of the inactive metabolite CAS X dialdehyde. These findings demonstrate that CAS X is susceptible to first-pass metabolism and is a substrate for specific carboxylesterases expressed in liver, which may contribute to a reduction in antitumor activity when administered by the oral route.-
Descrição: dc.descriptionNúcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS) Departamento de Física e Química Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo-
Descrição: dc.descriptionDepartamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo, Avenida Bandeirantes 3900-
Descrição: dc.descriptionNúcleo de Bioensaios Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE) Departamento de Química Orgânica Instituto de Química Universidade Do Estado de São Paulo-
Descrição: dc.descriptionDepartamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo-
Formato: dc.format282-291-
Idioma: dc.languageen-
Relação: dc.relationPlanta Medica-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectCasearia sylvestris-
Palavras-chave: dc.subjectcasearin X-
Palavras-chave: dc.subjectenzyme kinetics-
Palavras-chave: dc.subjectin vitro metabolism-
Palavras-chave: dc.subjectnatural product-
Palavras-chave: dc.subjectSalicaceae-
Título: dc.titleCharacterization of Casearin X Metabolism by Rat and Human Liver Microsomes-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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