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

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• 作者：Sussan Ghassabian^a ; Tristan Rawling^a ; Fanfan Zhou^a ; Munikumar R. Doddareddy^b ; Bruce N. Tattam^c ; David E. Hibbs^b ; Robert J. Edwards^d ; Pei H. Cui^a ; Michael Murray^a ; ^{michael.murray@sydney.edu.au}
• 关键词：CYP ; cytochrome P450 ; FMO ; flavin-containing monooxygenase ; HPLC ; high-performance liquid chromatography ; LC&ndash ; MS/MS ; liquid chromatography&ndash ; tandem mass spectrometry ; TKI ; tyrosine kinase inhibitor
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：15 July, 2012
• 卷：84
• 期：2
• 页码：215-223
• 文件大小：863 K

摘要

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 鈭?%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鈥?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 鈭?.4 脜 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.