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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.)

Myclobutanil enantioselective risk assessment in humans through in vitro CYP450 reactions: Metabolism and inhibition studies

Full text
Author(s):
Fonseca, Franciele S. [1] ; Carrao, Daniel B. [1] ; de Albuquerque, Nayara C. P. [1] ; Nardini, Viviani [1] ; Dias, Luis G. [1] ; da Silva, Rodrigo M. [2] ; Lopes, Norberto P. [2] ; de Oliveira, Anderson R. M. [1]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, Av Bandeirantes 3900, BR-14040901 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Nucleo Pesquisas Prod Nat & Sintet, Fac Ciencias Farmacaut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Food and Chemical Toxicology; v. 128, p. 202-211, JUN 2019.
Web of Science Citations: 2
Abstract

Myclobutanil is a chiral triazole fungicide that is employed worldwide. Although enantiomers have the same physical-chemical properties, they may differ in terms of activity, metabolism, and toxicity. This investigation consisted of in vitro enantioselective metabolism studies that employed a human model to assess the risks of myclobutanil in humans. A LC-MS/MS enantioselective method was developed and validated. The enzymatic kinetic parameters (V-MAX, K-Mapp, and CLINT) determined for in vitro rac-myclobutanil and S-(+)-myclobutanil metabolism revealed enantioselective differences. Furthermore, human CYP450 enzymes did not metabolize R-(-)-myelobutanil. The predicted in vivo toxicokinetic parameters indicated that S-(+)-myclobutanil may be preferentially eliminated by the liver and suffer the first-pass metabolism effect. However, because CYP450 did not metabolize R-(-)-myclobutanil, this enantiomer could reach the systemic circulation and stay longer in the human body, potentially causing toxic effects. The CYP450 isoforms CYP2C19 and CYP3A4 were involved in racmyclobutanil and S-(+)-myclobutanil metabolism. Although there were differences in the metabolism of the myclobutanil enantiomers, in vitro inhibition studies did not show significant enantioselective differences. Overall, the present investigation suggested that myclobutanil moderately inhibits CYP2D6 and CYP2C9 in vitro and strongly inhibits CYP3A and CYP2C19 in vitro. These results provide useful scientific information for myclobutanil risk assessment in humans. (AU)

FAPESP's process: 13/08166-5 - Interfacial chemistry: drugs, peptides and ezymes interactions with membrane models
Grantee:Iolanda Midea Cuccovia
Support type: Research Projects - Thematic Grants
FAPESP's process: 16/07597-0 - Development of chromatographic/electrophoretic methods to be further used in in vitro enzymatic inhibition and drug interaction of chiral pesticides
Grantee:Anderson Rodrigo Moraes de Oliveira
Support type: Regular Research Grants
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 type: 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 type: Regular Research Grants
FAPESP's process: 17/03204-7 - Development and application of coarse-graining force field in self-assembled systems
Grantee:Luis Gustavo Dias
Support type: Regular Research Grants