Enantioselective in vitro metabolism of the herbicide diclofop-methyl: Prediction of toxicokinetic parameters and reaction phenotyping

Author(s)

Barbetta, Maike Felipe Santos ; Perovani, Icaro Salgado ; Duarte, Leandro Oka ; de Oliveira, Anderson Rodrigo Moraes

• Document type: Journal article
• Source: Journal of Pharmaceutical and Biomedical Analysis; v. 235, p. 9-pg., 2023-10-25.

Abstract

Human exposure to contaminants of emerging concern, like pesticides, has increased in the past decades. Diclofop-methyl (DFM) is a chiral herbicide that is employed as a racemic mixture (rac-DFM) in soybean and other crops against wild oats. Studies have shown that DFM has enantioselective action (higher for R-DFM), degradation (faster for S-DFM), and metabolism, producing diclofop (DF) which is also a pesticide. Although toxic effects have been reported for DFM, information regarding how DFM affects humans is lacking, especially when its chirality is concerned. In this study, the in vitro metabolism of rac-DFM and its isolated enantiomers was assessed by using a human model based on human liver microsomes. The kinetic model and parameters were obtained, and the hepatic clearance (CLH) and hepatic extraction ratio (EH) were estimated. Enzyme phenotyping was carried out by employing carboxylesterase isoforms (CES 1 and CES 2). DFM was metabolized through positive homotropic cooperativity with slight preference for (-)-DFM metabolism to (-)-DF. CLH and EH were above 19.60 mL min- 1 kg- 1 and 98 % for all the monitored reactions, respectively, and CES 1 was the main enzyme underlying the metabolism. These findings point out that liver contributes to DFM metabolism, which is fast, resulting in nearly complete conversion to DF after exposition to DFM. (AU)

• 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: 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: 21/10098-4 - In vitro enantioselective evaluation of the effect of chiral pesticides on main human cytochrome P450 enzymes involved in drug metabolism: in vitro-in vivo correlation and prediction of pesticide-drug interaction
• Grantee: Anderson Rodrigo Moraes de Oliveira
• Support Opportunities: Regular Research Grants