Quantitative Evaluation of Drug-Drug Interaction Potentials by in vivo Information- Guided Prediction Approach

2015 ◽  
Vol 15 (8) ◽  
pp. 761-766 ◽  
Author(s):  
Feng Chen ◽  
Zhe-Yi Hu ◽  
Wei-Wei Jia ◽  
Jing-Tao Lu ◽  
Yuan-Sheng Zhao
2021 ◽  
Vol 22 ◽  
Author(s):  
Liyan Wang ◽  
Tingting Zhao ◽  
Yunxiang Wang ◽  
Banglian Hu ◽  
Jianfei Tao ◽  
...  

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. 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.


Pharmacology ◽  
2015 ◽  
Vol 95 (3-4) ◽  
pp. 133-138 ◽  
Author(s):  
Sai-Zhen Chen ◽  
Pei-Pei Pan ◽  
Shuang-Hu Wang ◽  
Jun Luo ◽  
Guo-Xin Hu ◽  
...  

2020 ◽  
Vol 45 (4) ◽  
pp. 433-444
Author(s):  
Roland Heinig ◽  
Michael Gerisch ◽  
Michaela Bairlein ◽  
Johannes Nagelschmitz ◽  
Stephanie Loewen

2015 ◽  
Vol 29 (6) ◽  
pp. 604-614 ◽  
Author(s):  
Edouard Ollier ◽  
Sophie Hodin ◽  
Thierry Basset ◽  
Sandrine Accassat ◽  
Laurent Bertoletti ◽  
...  

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