Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin

Summary:The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6α-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6α-hydroxypaclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC 50 values 4.25 ± 0.02 and 68.5 ± 3.3 μM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13 ± 0.11 μM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the Vmax (maximum velocity) and increased the Km value (substrate concentration yielding 50% of Vmax) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with coadministered drugs metabolized by this CYP.