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

Murray, M; Gillani, TB; Rawling, T; Nair, PC

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

Murray, M

Gillani, TB Rawling, T

Nair, PC

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Publication Type:: Journal Article
Citation:: AAPS Journal, 2019, 21 (6)
Issue Date:: 2019-11-01

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Field	Value	Language
dc.contributor.author	Murray, M https://orcid.org/0000-0002-4233-7619	en_US
dc.contributor.author	Gillani, TB	en_US
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586	en_US
dc.contributor.author	Nair, PC	en_US
dc.date.available	2019-08-16	en_US
dc.date.issued	2019-11-01	en_US
dc.identifier.citation	AAPS Journal, 2019, 21 (6)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/136777
dc.description.abstract	© 2019, American Association of Pharmaceutical Scientists. 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.	en_US
dc.relation.ispartof	AAPS Journal	en_US
dc.relation.isbasedon	10.1208/s12248-019-0374-2	en_US
dc.subject.classification	Pharmacology & Pharmacy	en_US
dc.title	Inhibition of Hepatic CYP2D6 by the Active N-Oxide Metabolite of Sorafenib	en_US
dc.type	Journal Article
utslib.citation.volume	6	en_US
utslib.citation.volume	21	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access
pubs.issue	6	en_US
pubs.publication-status	Published	en_US
pubs.volume	21	en_US

Abstract:

© 2019, American Association of Pharmaceutical Scientists. 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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http://hdl.handle.net/10453/136777