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 is a major enzyme in the elimination of oncology drugs like paclitaxel and imatinib. It has been reported that CYP2C8 inhibition by SOR in human liver microsomes is potentiated by NADPH-dependent biotransformation. This implicates a SOR metabolite in enhanced inhibition, although the identity of that metabolite is presently unclear. The present study evaluated the capacity of the major N-oxide metabolite of SOR (SNO) to inhibit CYP2C8-dependent paclitaxel 6α-hydroxylation. The IC50 of SNO against CYP2C8 activity was found to be 3.7-fold lower than that for the parent drug (14 μM versus 51 μM). In molecular docking studies, both SOR and SNO interacted with active site residues in CYP2C8, but four additional major hydrogen and halogen bonding interactions were identified between SNO and amino acids in the B–B′ loop region and helixes F’ and I that comprise the catalytic region of the enzyme. In contrast, the binding of both SOR and SNO to active site residues in the closely related human CYP2C9 enzyme was similar, as were the IC50s determined against CYP2C9-mediated losartan oxidation. These findings suggest that the active metabolite SNO could impair the elimination of coadministered drugs that are substrates for CYP2C8, and mediate toxic adverse events, perhaps in those individuals in whom SNO is formed extensively. •Paclitaxel 6α-hydroxylation by CYP2C8 was effectively inhibited by sorafenib N-oxide.•More CYP2C8 binding interactions were noted with the metabolite than with sorafenib.•B–B′ loop and F′ and I helix residues formed effective interactions with the N-oxide.•Sorafenib N-oxide could contribute to paclitaxel toxicity in cancer patients.