Supporting the Development of an Eco-Friendly R-(-)-Mefentrifluconazole: Evidence from Integrated Toxicokinetic...

Mefentrifluconazole (MEF) is a chiral triazole fungicide, with R-(-)-MEF exhibiting 5- to 473-fold greater fungicidal activity than S-(+)-MEF. Most enantiomer ecotoxicity data are derived from simple model species. This study investigated MEF stereoselectivity in rats via toxicokinetic modeling. Total excretion of both enantiomers was merely ∼12.80%, excluding excretion as a primary clearance route. S-(+)-MEF accumulated preferentially in the stomach and small intestinal tissues due to preferential absorption, whereas R-(-)-MEF predominated in plasma and other nongastrointestinal tissues (AUC R/S = 1.37-7.58). Unidirectional S → R configuration conversion (4.70-61.86%), coupled with metabolic interference by S-(+)-MEF, may account for the in vivo accumulation of R-(-)-MEF. For the first time at the enantiomer level, network toxicology and molecular docking demonstrated that S-(+)-MEF more severely disrupts the PI3K-Akt/MAPK pathways implicated in hepatotoxicity. Therefore, the use of high-activity, lower-toxicity R-(-)-MEF can enhance fungicidal efficiency, reduce application rates, and mitigate risks to human health and the environment.