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The AAPS Journal

, 21:107 | Cite as

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

  • Michael MurrayEmail author
  • Tina B. Gillani
  • Tristan Rawling
  • Pramod C. Nair
Research Article
  • 72 Downloads

Abstract

The multikinase inhibitor sorafenib (SOR) is used to treat patients with hepatocellular and renal carcinomas. SOR undergoes CYP-mediated biotransformation to a pharmacologically active N-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 dextromethorphan O-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 of H-bonding interactions was noted between the N-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 accumulates.

KEY WORDS

CYP2D6 inhibition dextromethorphan O-demethylation metabolite inhibition molecular docking sorafenib sorafenib N-oxide 

Abbreviations

AUC

area under the serum concentration versus time curve

Cmax

maximal serum concentration

CYP

cytochrome P450

DDI

drug-drug interaction

SOR

sorafenib

SNO

sorafenib N-oxide

SRS

substrate recognition site

Notes

Acknowledgments

Technical contributions in aspects of the study from Dr. S. Cui and Ms. K Bourget are also acknowledged. The supply of the human liver samples used in this study by Dr. J George is also gratefully acknowledged.

Funding Information

This study is financially supported by the Cancer Council NSW (grants RG09-14 and IG11-33). PCN is supported by the Flinders Centre for Innovation in Cancer (FCIC) and Flinders Medical Centre (FMC) Foundation through an Early Career Research Grant.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and HealthUniversity of SydneySydneyAustralia
  2. 2.School of Mathematical and Physical Sciences, Faculty of ScienceUniversity of Technology SydneyUltimoAustralia
  3. 3.Department of Clinical Pharmacology and Flinders Centre for Innovation in CancerCollege of Medicine and Public Health, Flinders UniversityBedford ParkAustralia

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