Title:In vitro Measurement and In vivo Prediction of Time-Dependent Inhibitory Effects of Three Tyrosine Kinase Inhibitors on CYP3A Activity
Volume: 22
Issue: 10
Author(s): Liyan Wang, Tingting Zhao, Yunxiang Wang, Banglian Hu, Jianfei Tao, Jinshan Ke, Tingfei Wei, Guangbo Ge, Qiang Meng, Changyuan Wang, Qi Liu, Huijun Sun, Jingjing Wu*Yanwei Chen*
Affiliation:
- Department of Clinical Pharmacology, Dalian Medical University, Dalian, Liaoning Province,China
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province,China
Keywords:
CYP3A, tyrosine kinase inhibitors, time-dependent inhibition, structure-inhibition relationship, in vitro-in vivo exploration, drugdrug
interaction.
Abstract:
Background: Imatinib, sunitinib, and gefitinib are the three most common tyrosine kinase inhibitors
(TKIs). However, their quantitative drug-drug interaction potentials In vivo and the relationship between their structure
and inhibitory activity remain unknown.
Objective: This study aimed to investigate the potential drug-drug interaction risk of three TKIs based on CYP3A.
Methods: 6β-Hydroxylated testosterone formation was selected to probe the CYP3A activity in human liver microsomes.
A molecular docking simulation was performed to explore the potential structural alerts.
Results: Imatinib exhibited the strongest inhibitory effect towards CYP3A, while the inhibitory potential of gefitinib
and sunitinib were comparable to each other but weaker than imatinib. IC50 shift assays demonstrated that the inhibitory
potential of all three TKIs was significantly increased after a 30-min preincubation with NADPH. The KI and
Kinact values of imatinib, sunitinib, and gefitinib were 3.75 μM and 0.055 min-1, 1.96 μM and 0.037 min-1, and 9.94
μM and 0.031 min-1, respectively. IVIVE results showed that there was a 1.3- to 43.1-fold increase in the AUC of
CYP3A-metabolizing drugs in the presence of the TKIs.
Conclusion: All three TKIs exhibited a typical irreversible inhibitory effect towards CYP3A. The presence of more
N-heterocycles and the resulting better binding confirmation of imatinib may have been responsible for its stronger
inhibitory effect than sunitinib and gefitinib. Therefore, caution should be taken when CYP3A-metabolizing drugs
are co-administrated with imatinib, sunitinib, or gefitinib.
