In vitro enantioselective study of the toxicokinetic effects of chiral fungicide tebuconazole in human liver microsomes

摘要: Abstract Tebuconazole (TEB) is a chiral triazole fungicide that globally marketed and used as racemic mixture to control plant pathogens. Due its use mixture, TEB may exhibit enantioselective toxicokinetics toward nontarget organisms, including humans. Therefore, the in vitro metabolism of by cytochrome P450 enzymes (CYP450) was studied using human liver microsomes, vivo toxicokinetic parameters were predicted. A new enantioselective, reversed-phase LC-MS/MS method developed validated analyze enantiomers main metabolite, 1-hydroxytebuconazole (TEBOH). In metabolic obtained, vitro-in extrapolations performed. Michaelis-Menten atypical biphasic kinetic profiles observed with total intrinsic clearance ranging from 53 19 mL min−1 mg−1. The extrapolation results showed first passage effect seems be negligible, hepatic extraction ratios 0.53 5.0 mL min−1 kg−1 2.7–25%, respectively. Preferential (+)-TEB rac-TEB (−)-TEB observed, preferential production (+)-TEBOH. Furthermore, reaction phenotyping studies revealed that, despite low pass TEB, multiple CYP450 isoforms involved when TEBOH generated, mainly CYP3A4 CYP2C9, which makes accumulation body more difficult due pathways.