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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Chemico-Biological Interactions; v. 345, AUG 25 2021.
• Citações Web of Science: 1

Resumo

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)

• 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: 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: 19/12149-5 - Avaliação in vitro do potencial inibitório do praguicida quiral etofumesato sobre as principais enzimas do citocromo P450 envolvidas no metabolismo de fármacos
• Beneficiário: Jade Lorena Mariano Bucci
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 20/02139-0 - Avaliação de risco do praguicida quiral protioconazol em modelos humanos: correlação in vitro-in vivo, predição de interação medicamentosa e estudos de cito- e genotoxicidade
• Beneficiário: Icaro Salgado Perovani
• Modalidade de apoio: Bolsas no Brasil - Doutorado