In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes

Abstract

Growing human demand for food has culminated in increased use of pesticides worldwide. Prothioconazole (PTC), a profungicide, is bioactivated by metabolic PTC oxidation to prothioconazole-desthio (D-PTC). Here, the in vitro phase I metabolism of PTC to D-PTC in human liver microsomes and human CYP450 forms was studied. The kinetic parameters for the formation of (+)-D-PTC (KM = 1.2 μmol L−1, VMAX = 1.7 pmol min−1 mg−1), (−)-D-PTC (KM = 7 μmol L−1, VMAX = 5.1 pmol min−1 mg−1), and both D-PTC enantiomers (KM = 9 μmol L−1, VMAX = 7 pmol min−1 mg−1) from rac-PTC indicated an enantioselective behavior. Formation of the enantiomer (+)-D-PTC was twice more extensive than the formation of the enantiomer (−)-D-PTC. Furthermore, CLH prediction revealed the same enantioselective behavior. The phenotyping study indicated that CYP2C19 was the sole CYP450 form accounting for the metabolism of PTC. The estimated apparent distribution volume of PTC was predicted as 2 L kg−1. This study showed that D-PTC may be formed in the human organism due to hepatic metabolism of PTC, mediated by CYP2C19 and that the enantiomer (+)-D-PTC is preferentially formed. However, it was not extensively formed (~1%). Considering a risk assessment point of view, this study provided positive evidence of PTC safety.