![Sample our Medicine, Dentistry, Nursing & Allied Health journals, sign in here to start your FREE access for 14 days]({"type":"image" , "src" : "/sda/5944/TOC-Subject-Sample-2021-Medicine-Dentistry-Nursing-Allied-Health.jpg"})
Abstract
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs).
2. The results showed that 100 μM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver–Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 2.3, 0.07 and 4.4 μM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively.
3. In vitro–in vivo extrapolation (IVIVE) showed that [I]/Ki value was calculated to be 0.004, 0.14 and 0.002 for UGT1A1, UGT-1A3 and UGT-2B7, respectively. Therefore, high DDI potential existed between everolimus and clinical drugs mainly undergoing UGT1A3-catalyzed glucuronidation.
Acknowledgements
This work was supported by the project for the National Key Research and Development Program (2016YFC0903100, 2016YFC0903102), National Natural Science Foundation of China (No. 81672961, 81602850), individualized diagnosis and treatment of colorectal cancer (No. LNCCC-B05-2015), The 13th five-year plan and TMU talent project (11601501/2016KJ0313), Foundation of Committee on Science and Technology of Tianjin (Grant No. 15JCYBJC54700), the China Postdoctoral Science Foundation (2016M590210), Tianjin Health Bureau Science Foundation Key Project (2014KR14, 16KG154) and Tianjin Project of Thousand Youth Talents.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.