CYP450 Metabolism of a Semisynthetic Naphthoquinone, an Anticancer Drug Candidate, by Human Liver Microsomes

Registro completo de metadados
MetadadosDescriçãoIdioma
Autor(es): dc.contributorUniv Fed Amazonas-
Autor(es): dc.contributorUniversidade de São Paulo (USP)-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorUniversidade Federal Fluminense (UFF)-
Autor(es): dc.creatorCosta, Edna M. A.-
Autor(es): dc.creatorCarrao, Daniel B.-
Autor(es): dc.creatorBucci, Jade L. M.-
Autor(es): dc.creatorOliveira, Anderson R. M. [UNESP]-
Autor(es): dc.creatorMachado, Tallita M.-
Autor(es): dc.creatorFerreira, Vitor F.-
Autor(es): dc.creatorLima, Emerson S.-
Autor(es): dc.creatorVasconcellos, Marne C.-
Autor(es): dc.creatorMagalhaes, Igor R. S.-
Data de aceite: dc.date.accessioned2022-08-04T21:59:20Z-
Data de disponibilização: dc.date.available2022-08-04T21:59:20Z-
Data de envio: dc.date.issued2022-04-28-
Data de envio: dc.date.issued2022-04-28-
Data de envio: dc.date.issued2022-02-21-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.21577/0103-5053.20220034-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/218820-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/218820-
Descrição: dc.descriptionCNFD (6b,7-dihydro-5H-cyclopenta[b]naphtho[2,1-d]furan-5,6(9aH)-dione) is a semisynthetic naphthoquinone derived from lawsone that has cytotoxic action in different tumor lines and anticancer activity in vivo. Therefore, this molecule is a relevant candidate for drug development, but there is still no information on its human metabolism and systemic elimination. This study aimed to investigate the in vitro metabolism of this naphthoquinone by human liver microsomes. Initially, in order to determine the in vitro enzymatic kinetic parameters, a high performance liquid chromatography (HPLC) method to quantify the CNFD was developed and validated. In addition, the enzymatic kinetic data, the predicted pharmacokinetic in vivo parameters and the phenotyping study were presented. The main metabolism sites and metabolites have been suggested in silico. The developed HPLC method was linear, reproducible, selective, accurate, and stable. The enzymatic kinetic parameters revealed a sigmoidal profile. In vitro to in vivo extrapolation hepatic metabolic clearance was 10.39 mL min-1 kg-1 protein and the liver extraction rate was 51%. The clearance in vivo associated with a hepatic extraction ratio indicates that the hepatic metabolism is the main route of elimination. Although all cytochrome P450 enzymes evaluated metabolized CNFD, CYP2C9 and CYP3A4 showed higher metabolic capacity. For the first time, metabolism studies of CNFD were demonstrated.-
Descrição: dc.descriptionConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)-
Descrição: dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionUniv Fed Amazonas, Fac Ciencias Farmaceut, Nucl Estudos Farmacocinet, BR-69077000 Manaus, AM, Brazil-
Descrição: dc.descriptionUniv Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, BR-14040901 Ribeirao Preto, SP, Brazil-
Descrição: dc.descriptionUniv Estadual Paulista UNESP, Avaliacao Toxicol & Remocao Contaminantes Emergen, Inst Quim, Inst Nacl Tecnol Alternat Deteccao, CP 355, BR-14800900 Araraquara, SP, Brazil-
Descrição: dc.descriptionUniv Fed Amazonas, Fac Ciencias Farmaceut, Lab Atividade Biol, BR-69077000 Manaus, AM, Brazil-
Descrição: dc.descriptionUniv Fed Fluminense, Lab Sintese Carboidratos & Nucl, BR-24220900 Niteroi, RJ, Brazil-
Descrição: dc.descriptionUniv Estadual Paulista UNESP, Avaliacao Toxicol & Remocao Contaminantes Emergen, Inst Quim, Inst Nacl Tecnol Alternat Deteccao, CP 355, BR-14800900 Araraquara, SP, Brazil-
Descrição: dc.descriptionCNPq: 14/2014-
Descrição: dc.descriptionFAPESP: 2016/15680-5-
Descrição: dc.descriptionFAPESP: 2018/07534-4-
Descrição: dc.descriptionCNPq: 465571/2014-0-
Descrição: dc.descriptionCAPES: 001-
Formato: dc.format9-
Idioma: dc.languageen-
Publicador: dc.publisherSoc Brasileira Quimica-
Relação: dc.relationJournal Of The Brazilian Chemical Society-
???dc.source???: dc.sourceWeb of Science-
Palavras-chave: dc.subjectlawsone-
Palavras-chave: dc.subjectdrug development-
Palavras-chave: dc.subjectbiotransformation-
Palavras-chave: dc.subjectpharmacokinetics-
Palavras-chave: dc.subjectpreclinical drug evaluation-
Título: dc.titleCYP450 Metabolism of a Semisynthetic Naphthoquinone, an Anticancer Drug Candidate, by Human Liver Microsomes-
Tipo de arquivo: dc.typelivro digital-
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