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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY; v. 181, p. 96-105, OCT 15 2019.
• Web of Science Citations: 1

Abstract

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)

• FAPESP's process: 14/50945-4 - INCT 2014: National Institute for Alternative Technologies of Detection, Toxicological Evaluation and Removal of Micropollutants and Radioactivies
• Grantee: Maria Valnice Boldrin
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/03204-7 - Development and application of coarse-graining force field in self-assembled systems
• Grantee: Luis Gustavo Dias
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/07534-4 - Development of chromatographic / electrophoretic methods to be further applied in in vitro enzymatic inhibition studies and prediction of drug interactions of chiral pesticides - Phase 2
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08166-5 - Interfacial chemistry: drugs, peptides and ezymes interactions with membrane models
• Grantee: Iolanda Midea Cuccovia
• Support Opportunities: Research Projects - Thematic Grants