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

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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.

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Abbreviations

AUC:

area under the serum concentration versus time curve

C max :

maximal serum concentration

CYP:

cytochrome P450

DDI:

drug-drug interaction

SOR:

sorafenib

SNO:

sorafenib N-oxide

SRS:

substrate recognition site

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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

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.

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Authors and Affiliations

  1. Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia

    Michael Murray & Tina B. Gillani

  2. School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007, Australia

    Tristan Rawling

  3. Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, College of Medicine and Public Health, Flinders University, Bedford Park, SA, 5042, Australia

    Pramod C. Nair

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Murray, M., Gillani, T.B., Rawling, T. et al. Inhibition of Hepatic CYP2D6 by the Active N-Oxide Metabolite of Sorafenib. AAPS J 21, 107 (2019). https://doi.org/10.1208/s12248-019-0374-2

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