In:
Fundamental & Clinical Pharmacology, Wiley, Vol. 28, No. 5 ( 2014-10), p. 551-582
Kurzfassung:
Kinase inhibitors ( KI s) represent an important group of anticancer drugs, and many of them are substrates and inhibitors of human cytochrome P450s ( CYP s), raising the potential of harmful drug interactions. This study investigated the effect of a library of KI s ( n = 91) including 11 FDA ‐approved KI s on human CYP 1A2, 2D6, 2C9, and 3A4 using high‐throughput screening kits and the binding modes with CYP s using the Discovery Studio program 3.1. The KI s exhibited differential inhibitory effect on CYP 1A2, 2D6, 2C9, and 3A4, while some of them showed activating effect on CYP 2C9 and 3A4. For example, SP 600125 was a potent inhibitor for CYP 1A2, but enhanced the activity of CYP 2C9 fourfolds. Among the 80 KI s that are not used clinically, about 13% showed significant inhibition to CYP s. Nilotinib, sunitinib, and imatinib were found to be potent CYP 1A2 inhibitor. Our docking studies have demonstrated the importance of multiple amino acid residues in the active sites of CYP 1A2, 2C9, 2D6, and 3A4 in binding with various KI s. Finally, the in vitro data were used to predict potential KI –drug interactions. These findings indicate that many KI s can serve as CYP inhibitors, and further studies are needed to examine the clinical impact.
Materialart:
Online-Ressource
ISSN:
0767-3981
,
1472-8206
DOI:
10.1111/fcp.2014.28.issue-5
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2014
ZDB Id:
2006242-4
SSG:
15,3