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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

In vitro enantioselective study of the toxicokinetic effects of chiral fungicide tebuconazole in human liver microsomes

Texto completo
Autor(es):
Habenschus, Maisa Daniela [1] ; Nardini, Viviani [1] ; Dias, Luis Gustavo [1] ; Rocha, Bruno Alves [2] ; Barbosa, Jr., Fernando [2] ; Moraes de Oliveira, Anderson Rodrigo [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, Ave Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Lab Toxicol & Essencialidade Met, BR-14049903 Ribeirao Preto, SP - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY; v. 181, p. 96-105, OCT 15 2019.
Citações Web of Science: 1
Resumo

Tebuconazole (TEB) is a chiral triazole fungicide that is globally marketed and used as a racemic mixture to control plant pathogens. Due to its use as a racemic mixture, TEB may exhibit enantioselective toxicokinetics toward nontarget organisms, including humans. Therefore, the in vitro enantioselective metabolism of TED by cytochrome P450 enzymes (CYP450) was studied using human liver microsomes, and the in vivo toxicokinetic parameters were predicted. A new enantioselective, reversed-phase LC-MS/MS method was developed and validated to analyze the enantiomers of TEB and its main metabolite, 1-hydroxytebuconazole (TEBOH). In vitro metabolic parameters were obtained, and in vitro-in vivo extrapolations were performed. Michaelis-Menten and atypical biphasic kinetic profiles were observed with a total intrinsic clearance ranging from 53 to 19 mL min(-1) mg(-1). The in vitro-in vivo extrapolation results showed that TEB first passage effect by the liver seems to be negligible, with hepatic clearance and extraction ratios ranging from 0.53 to 5.0 mL min(-1) kg(-1) and 2.7-25%, respectively. Preferential metabolism of (+)-TEB to rac-TEB and (-)-TEB was observed, with preferential production of (+)-TEBOH. Furthermore, reaction phenotyping studies revealed that, despite the low hepatic clearance in the first pass metabolism of TEB, multiple human CYP450 isoforms were involved in TEB metabolism when TEBOH enantiomers were generated, mainly CYP3A4 and CYP2C9, which makes TEB accumulation in the human body more difficult due to multiple metabolic pathways. (AU)

Processo FAPESP: 13/08166-5 - Química em interfaces: interações de fármacos, peptídios e enzimas com membranas modelos
Beneficiário:Iolanda Midea Cuccovia
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 18/07534-4 - Desenvolvimento de métodos cromatográficos/eletroforéticos para posterior aplicação em estudos in vitro de inibição enzimática e predição de interações medicamentosas de praguicidas quirais - Fase 2
Beneficiário:Anderson Rodrigo Moraes de Oliveira
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 14/50945-4 - INCT 2014: Instituto Nacional de Tecnologias Alternativas para Detecção, Avaliação Toxicológica e Remoção de Micropoluentes e Radioativos
Beneficiário:Maria Valnice Boldrin
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 17/03204-7 - Desenvolvimento e aplicação de campo de força coarse-graining em sistemas auto-organizados
Beneficiário:Luis Gustavo Dias
Linha de fomento: Auxílio à Pesquisa - Regular