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

Details

Serval ID
serval:BIB_49F3FF816FB5
Type
Article: article from journal or magazin.
Collection
Publications
Title
Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4.
Journal
The AAPS journal
Author(s)
Ghassabian S., Gillani T.B., Rawling T., Crettol S., Nair P.C., Murray M.
ISSN
1550-7416 (Electronic)
ISSN-L
1550-7416
Publication state
Published
Issued date
09/01/2019
Peer-reviewed
Oui
Volume
21
Number
2
Pages
15
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
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 (K <sub>i</sub> s 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
Pubmed
Web of science
Create date
05/03/2019 9:23
Last modification date
20/08/2019 13:57
Usage data