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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Enantioselective inhibition of human CYP2C19 by the chiral pesticide ethofumesate: Prediction of pesticide-drug interactions in humans

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Author(s):
Perovani, Icaro Salgado [1] ; Mariano Bucci, Jade Lorena [1] ; Carrao, Daniel Blascke [1] ; Santos Barbetta, Maike Felipe [1] ; da Silva, Rodrigo Moreira [2] ; Lopes, Norberto Peporine [2] ; Moraes de Oliveira, Anderson Rodrigo [1, 3]
Total Authors: 7
Affiliation:
[1] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, Av Bandeirantes, 3900, Ribeir Ao Preto, BR-14040901 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias Biomol, Nucleo Pesquisas Prod Nat & Sinteticos, BR-14090903 Ribeirao Preto, SP - Brazil
[3] Unesp Inst Chem, Toxicol Evaluat & Removal Micropollutants & Radio, Natl Inst Alternat Technol Detect, POB 355, BR-14800900 Araraquara, SP - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Chemico-Biological Interactions; v. 345, AUG 25 2021.
Web of Science Citations: 1
Abstract

Ethofumesate is a chiral herbicide that may display enantioselective behavior in humans. For this reason, the enantioselective potential of ethofumesate and its main metabolite ethofumesate-2-hydroxy to cause pesticide-drug interactions on cytochrome P450 forms (CYPs) has been evaluated by using human liver microsomes. Among the evaluated CYPs, CYP2C19 had its activity decreased by the ethofumesate racemic mixture (rac-ETO), (+)-ethofumesate ((+)-ETO), and (-)-ethofumesate ((-)-ETO). CYP2C19 inhibition was not time-dependent, but a strong inhibition potential was observed for rac-ETO (IC50 = 5 +/- 1 mu mol L-1), (+)-ETO (IC50 = 1.6 +/- 0.4 mu mol L-1), and (-)-ETO (IC50 = 1.8 +/- 0.4 mu mol L-1). The reversible inhibition mechanism was competitive, and the inhibition constant (KO values for rac-ETO (2.6 +/- 0.4 mu mol L-1), (+)-ETO (1.5 +/- 0.2 mu mol L-1), and (-)-ETO (0.7 +/- 0.1 mu mol L-1) were comparable to the Ki values of strong CYP2C19 inhibitors. Inhibition of CYP2C19 by ethofumesate was enantioselective, being almost twice higher for (-)-ETO than for (+)-ETO, which indicates that this enantiomer may be a more potent inhibitor of this CYP form. For an in vitro-in vivo correlation, the Food and Drug Administration's (FDA) guideline on the assessment of drug-drug interactions used in the early stages of drug development was used. The FDA's R-1 values were estimated on the basis of the obtained ethofumesate K-i and distribution volume, metabolism, unbound plasma fraction, gastrointestinal and dermal absorption data available in the literature. The correlation revealed that ethofumesate probably inhibits CYP2C19 in vivo for both chronic (oral) and occupational (dermal) exposure scenarios. (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: 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: 19/12149-5 - In vitro evaluation of the inhibitory potential of the chiral pesticide etofumesate on the main cytochrome P450 enzymes involved in drug metabolism
Grantee:Jade Lorena Mariano Bucci
Support Opportunities: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 20/02139-0 - Risk assessment of the chiral pesticide prothioconazole in human models: in vitro-in vivo correlation, prediction of drug-pesticide interaction and cyto- and genotoxicity studies
Grantee:Icaro Salgado Perovani
Support Opportunities: Scholarships in Brazil - Doctorate