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

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]

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

• 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: 14/50945-4 - INCT 2014: Instituto Nacional de Tecnologias Alternativas para Detecção, Avaliação Toxicológica e Remoção de Micropoluentes e Radioativos
• Beneficiário: Maria Valnice Boldrin
• Modalidade de apoio: 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
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• 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
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/08166-5 - Química em interfaces: interações de fármacos, peptídios e enzimas com membranas modelos
• Beneficiário: Iolanda Midea Cuccovia
• Modalidade de apoio: Auxílio à Pesquisa - Temático