Functional Characterization of 22 CYP3A4 Protein Variants to Metabolize Ibrutinib In Vitro

Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in human beings. Ibrutinib is an anticancer drug and primarily metabolized by CYP3A...

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Bibliographic Details
Published in:Basic & clinical pharmacology & toxicology 2018-04, Vol.122 (4), p.383-387
Main Authors: Xu, Ren‐ai, Wen, Jian, Tang, Pengfei, Wang, Chenchen, Xie, Saili, Zhang, Bo‐wen, Zhou, Quan, Cai, Jian‐ping, Hu, Guo‐xin
Format: Article
Language:English
Subjects:
Adults
Antineoplastic Agents - metabolism
Antineoplastic Agents - therapeutic use
CYP3A4 protein
Cytochrome
Cytochrome P-450 CYP3A - genetics
Cytochrome P-450 CYP3A - metabolism
Cytochrome P450
Enzymatic activity
Enzyme activity
Enzyme Assays
Enzymes
Humans
Lymphoproliferative Disorders - drug therapy
Metabolism
Microsomes - enzymology
Polymorphism, Genetic
Precision Medicine - methods
Protein turnover
Proteins
Pyrazoles - metabolism
Pyrazoles - therapeutic use
Pyrimidines - metabolism
Pyrimidines - therapeutic use
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Substrates
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Summary:Cytochrome P450 3A4 (CYP3A4) is quantitatively the most important P450 enzyme in adults. It is suggested that CYP3A4 genetic polymorphisms may influence the rate of the metabolism and elimination of CYP3A4 substrates in human beings. Ibrutinib is an anticancer drug and primarily metabolized by CYP3A4. The aim of this study was to systematically investigate the effects of 22 CYP3A4 protein variants on the metabolism of ibrutinib in vitro. When compared with wild‐type CYP3A4.1, two variants (CYP3A4.17 and CYP3A4.24) had no detectable enzyme activity; five variants (CYP3A4.10, .11, .18, .23 and .33) exhibited no significant differences; another five variants (CYP3A4.3, .4, .9, .19 and .34) showed increased intrinsic clearance values, while the remaining nine variants (CYP3A4.2, .5, .14, .15, .16, .28, .29, .31 and .32) displayed decreased enzymatic activities in different degrees. As the first study of 22 CYP3A4 protein variants in ibrutinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism and elimination of ibrutinib and also offer a reference to the personalized treatment of ibrutinib in clinic.
ISSN:1742-7835
1742-7843
DOI:10.1111/bcpt.12934