Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite

The tyrosine kinase inhibitor sorafenib (SOR) is being used increasingly in combination with other anticancer agents like paclitaxel, but this increases the potential for drug toxicity. SOR inhibits several human CYPs, including CYP2C8, which a major enzyme elimination of oncology drugs paclitaxel and imatinib. It has been reported that CYP2C8 inhibition by liver microsomes potentiated NADPH-dependent biotransformation. This implicates metabolite enhanced inhibition, although identity presently unclear. present study evaluated capacity N-oxide (SNO) to inhibit CYP2C8-dependent 6?-hydroxylation. IC50 SNO against activity was found be 3.7-fold lower than parent (14 ?M versus 51 ?M). In molecular docking studies, both interacted active site residues four additional hydrogen halogen bonding interactions were identified between amino acids B–B? loop region helixes F’ I comprise catalytic enzyme. contrast, binding closely related CYP2C9 similar, as IC50s determined CYP2C9-mediated losartan oxidation. These findings suggest could impair coadministered are substrates mediate toxic adverse events, perhaps those individuals whom formed extensively.