Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4
The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. In this study undertaken in hepatic microsomes from individual donors, we assessed the possibility that SNO might contribute to pharmacokinetic interactions mediated by SOR. Enzyme kinetics of CYP3A4-mediated midazolam 1′-hydroxylation in individual human hepatic microsomes were analyzed by non-linear regression and appropriate replots. Thus, SNO and SOR were linear-mixed inhibitors of microsomal CYP3A4 activity (Kis 15 ± 4 and 33 ± 14 μM, respectively). To assess these findings, further molecular docking studies of SOR and SNO with the 1TQN crystal structure of CYP3A4 were undertaken. SNO elicited a larger number of interactions with key amino acid residues located in substrate recognition sequences of the enzyme. In the optimal docking pose, the N-oxide moiety of SNO was also found to interact directly with the heme moiety of CYP3A4. These findings suggest that SNO could contribute to pharmacokinetic interactions involving SOR, perhaps in individuals who produce high circulating concentrations of the metabolite.
KEY WORDSCYP3A4 inhibition metabolite inhibition midazolam 1′-hydroxylation sorafenib sorafenib N-oxide
area under the serum concentration versus time curve
maximal serum concentration
substrate recognition sequence
SC acknowledges Fellowship support from the Swiss National Science Foundation. PCN acknowledges the Flinders Centre for Innovation in Cancer (FCIC) and Flinders Medical Centre (FMC) Foundation for an Early Career Research Grant. Technical contributions in aspects of the study from Dr. S. Cui, Ms. K Bourget, Mr. E Li and Ms. L Pham are also acknowledged. The supply of several of the human liver samples used in this study by Dr. J George is also gratefully acknowledged.
This study is financially supported by the Cancer Council NSW (grants RG09-14 and IG11-33).
Compliance with Ethical Standards
Experiments in human liver microsomes were approved by ethics committees of the Western Sydney Area Health Service and the University of Sydney, according to the Declaration of Helsinki.
Conflicts of Interest
The authors declare that they have no conflict of interest.
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