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

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dc.contributor.authorPerovani, Icaro Salgado
dc.contributor.authorMariano Bucci, Jade Lorena
dc.contributor.authorCarrão, Daniel Blascke
dc.contributor.authorSantos Barbetta, Maike Felipe
dc.contributor.authorMoreira da Silva, Rodrigo
dc.contributor.authorLopes, Norberto Peporine
dc.contributor.authorMoraes de Oliveira, Anderson Rodrigo [UNESP]
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2022-04-29T08:45:32Z
dc.date.available2022-04-29T08:45:32Z
dc.date.issued2021-08-25
dc.description.abstractEthofumesate 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 μmol L−1), (+)-ETO (IC50 = 1.6 ± 0.4 μmol L−1), and (−)-ETO (IC50 = 1.8 ± 0.4 μmol L−1). The reversible inhibition mechanism was competitive, and the inhibition constant (Ki) values for rac-ETO (2.6 ± 0.4 μmol L−1), (+)-ETO (1.5 ± 0.2 μmol L−1), and (−)-ETO (0.7 ± 0.1 μmol 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 R1 values were estimated on the basis of the obtained ethofumesate Ki 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.en
dc.description.affiliationDepartamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo
dc.description.affiliationNúcleo de Pesquisas de Produtos Naturais e Sintéticos Departamento de Ciências Biomoleculares Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo
dc.description.affiliationNational Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355
dc.description.affiliationUnespNational Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdFAPESP: 2014/50945-4
dc.description.sponsorshipIdFAPESP: 2016/14668-7
dc.description.sponsorshipIdFAPESP: 2018/07534-4
dc.description.sponsorshipIdFAPESP: 2019/12149-5
dc.description.sponsorshipIdFAPESP: 2020/02139-0
dc.description.sponsorshipIdCNPq: 465571/2014-0
dc.identifierhttp://dx.doi.org/10.1016/j.cbi.2021.109552
dc.identifier.citationChemico-Biological Interactions, v. 345.
dc.identifier.doi10.1016/j.cbi.2021.109552
dc.identifier.issn1872-7786
dc.identifier.issn0009-2797
dc.identifier.scopus2-s2.0-85108419709
dc.identifier.urihttp://hdl.handle.net/11449/231463
dc.language.isoeng
dc.relation.ispartofChemico-Biological Interactions
dc.sourceScopus
dc.subjectCYP inhibition
dc.subjectCYP2C19
dc.subjectEnantioselective
dc.subjectEthofumesate
dc.subjectHuman liver microsomes
dc.subjectPesticide-drug interaction
dc.titleEnantioselective inhibition of human CYP2C19 by the chiral pesticide ethofumesate: Prediction of pesticide-drug interactions in humansen
dc.typeArtigo

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