title: Prediction of the likelihood of drug interactions with kinase inhibitors based on in vitro and computational studies.
abstract: Kinase inhibitors (KIs) represent an important group of anticancer drugs, and many of them are substrates and inhibitors of human cytochrome P450s (CYPs), raising the potential of harmful drug interactions. This study investigated the effect of a library of KIs (n = 91) including 11 FDA-approved KIs on human CYP1A2, 2D6, 2C9, and 3A4 using high-throughput screening kits and the binding modes with CYPs using the Discovery Studio program 3.1. The KIs exhibited differential inhibitory effect on CYP1A2, 2D6, 2C9, and 3A4, while some of them showed activating effect on CYP2C9 and 3A4. For example, SP 600125 was a potent inhibitor for CYP1A2, but enhanced the activity of CYP2C9 fourfolds. Among the 80 KIs that are not used clinically, about 13% showed significant inhibition to CYPs. Nilotinib, sunitinib, and imatinib were found to be potent CYP1A2 inhibitor. Our docking studies have demonstrated the importance of multiple amino acid residues in the active sites of CYP1A2, 2C9, 2D6, and 3A4 in binding with various KIs. Finally, the in vitro data were used to predict potential KI-drug interactions. These findings indicate that many KIs can serve as CYP inhibitors, and further studies are needed to examine the clinical impact.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Wang
authors.forename: Jiazhi
authors.initials: J
authors.lastname: Sun
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Howell
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhou
authors.forename: Zhi-Xu
authors.initials: ZX
authors.lastname: He
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
authors.forename: Helen
authors.initials: H
authors.lastname: Chew
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.forename: Jagat R
authors.initials: JR
authors.lastname: Kanwar
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D016013:Likelihood Functions; D047428:Protein Kinase Inhibitors / Q000378:metabolism*
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D047428:Protein Kinase Inhibitors
keywords: CYP3A4; drug interaction; high-throughput; kinase inhibitor; molecular docking; toxicity