Inhibition of Hepatic CYP2D6 by the Active N -Oxide Metabolite of Sorafenib

AbstractThe multikinase inhibitor sorafenib (SOR) is used to treat patients with hepatocellular and renal carcinomas. SOR undergoes CYP-mediated biotransformation to a pharmacologically activeN-oxide metabolite (SNO) that has been shown to accumulate to varying extents in individuals. Kinase inhibitors like SOR are frequently coadministered with a range of other drugs to improve the efficacy of anticancer drug therapy and to treat comorbidities. Recent evidence has suggested that SNO is more effective than SOR as an inhibitor of CYP3A4-mediated midazolam 1 ′-hydroxylation. CYP2D6 is also reportedly inhibited by SOR. The present study assessed the possibility that SNO might contribute to CYP2D6 inhibition. The inhibition kinetics of CYP2D6-mediated dextromethorphanO-demethylation were analyzed in human hepatic microsomes, with SNO found to be ~  19-fold more active than SOR (Kis 1.8  ± 0.3 μM and 34 ± 11 μM, respectively). Molecular docking studies of SOR and SNO were undertaken using multiple crystal structures of CYP2D6. Both molecules mediated interactions with key amino acid residues in putative substrate recognition sites of CYP2D6. However, a larger number o f H-bonding interactions was noted between theN-oxide moiety of SNO and active site residues that account for its greater inhibition potency. These findings suggest that SNO has the potential to contribute to pharmacokinetic interactions involving SOR, perhaps in those individuals in whom SNO accumu...
Source: The AAPS Journal - Category: Drugs & Pharmacology Source Type: research