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1. Biochem Pharmacol. 2012 Apr 10. [Epub ahead of print]

Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized

Ghassabian S, Rawling T, Zhou F, Doddareddy MR, Tattam BN, Hibbs DE, Edwards RJ,
Cui PH, Murray M.

Pharmacogenomics and Drug Development Group, University of Sydney, Sydney, NSW
2006, Australia.

The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver
and renal cancers but adverse effects may necessitate dose interruption and
under-dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome
P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites.
However, although CYPs are major determinants of efficacy and toxicity the roles
of these enzymes in the formation of multiple sorafenib metabolites are unclear.
In the present study CYP-mediated pathways of sorafenib oxidation in human liver
were evaluated. cDNA-expressed CYP3A4 was the major catalyst in the formation of
the principal N-oxide and N-hydroxymethyl metabolites of sorafenib, as well as
the minor N-desmethyl metabolite. In contrast, CYP3A5 exhibited only ∼5% of the
activity of CYP3A4 and eleven other CYPs and three flavin-containing
monooxygenases were inactive. In human hepatic microsomes metabolite formation
was correlated with CYP3A4-mediated midazolam 1'-hydroxylation, but not with
other CYP-specific substrate oxidations. In accord with these findings the CYP3A4
inhibitor ketoconazole selectively inhibited microsomal sorafenib oxidation
pathways. From computational modeling studies atoms in the structure of sorafenib
that undergo biotransformation were within ∼5.4Å of the CYP3A4 heme. Important
hydrogen bonding interactions between sorafenib and amino acids Ser-119 and
Glu-374 in the active center of CYP3A4 were identified. These findings indicate
that sorafenib is oxidized selectively by human CYP3A4. This information could be
adapted in individualized approaches to optimize sorafenib safety and efficacy in
cancer patients.

Copyright © 2012. Published by Elsevier Inc.

PMID: 22513143 [PubMed - as supplied by publisher]