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AAPS J. 2019 Jan 9;21(2):15. doi: 10.1208/s12248-018-0262-1.

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4.

Author information

1
Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.
2
School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
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.
4
Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia. michael.murray@sydney.edu.au.

Abstract

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.

KEYWORDS:

CYP3A4 inhibition; metabolite inhibition; midazolam 1′-hydroxylation; sorafenib; sorafenib N-oxide

PMID:
30627802
DOI:
10.1208/s12248-018-0262-1

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