Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms |
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| Authors: | Ai‐Lun Ma Shu‐Fen Wang Dan Lu Cui‐Min Hu Yan‐Yan Zhang Haina Wang Lingyun Hu Jun Deng Kun Yang Zhong‐Ze Fang |
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| Affiliation: | 1. School of Pharmaceutical Science and Technology, Key Laboratory for Modern Drug Delivery & High‐Efficiency, Tianjin University, Tianjin, People's Republic of China;2. Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, People's Republic of China;3. Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, People's Republic of China;4. Tianjin Life Science Research Center, Department of Microbiology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People's Republic of China;5. Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian, People's Republic of China;6. College of Pharmaceutical Sciences, Shandong University, Jinan, People's Republic of China;7. Shandong Cancer Hospital and Institute, Shandong, People's Republic of China;8. Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University, Tianjin, People's Republic of China |
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| Abstract: | Rivaroxaban is an oral direct factor Xa (FXa) inhibitor clinically used to prevent and treat thromboembolic disorders. Drug–drug interaction (DDI) exist for rivaroxaban and the inhibitors of CYP3A4/5. This study aims to investigate the inhibition of rivaroxaban and its derivatives with a chiral center towards UDP‐glucuronosyltransferases (UGTs). Chemical synthesis was performed to obtain rivaroxaban derivatives with different chiral centers. UGTs supersomes‐catalyzed 4‐methylumbelliferone (4‐MU) glucuronidation was employed to evaluate the inhibition potential towards various UGT isoforms. A significant influence of rivaroxaban derivatives towards UGT1A3 was observed. Chiral centers produce different effects towards the effect of four pairs of rivaroxaban derivatives towards UGT1A3 activity, with stronger inhibition potential of S1 than R1, but stronger inhibition capability of R2, R3, R4 than S2, S3, and S4. Competitive inhibition of R3 and R4 towards UGT1A3 was demonstrated by Dixon and Lineweaver‐Burk plots. In conclusion, the significant influence of rivaroxaban derivatives towards UGT1A3's activity was demonstrated in the present study. The chirality centers highly affected the inhibition behavior of rivaroxaban derivatives towards UGT1A3. Chirality 27:936–943, 2015. © 2015 Wiley Periodicals, Inc. |
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| Keywords: | rivaroxaban UDP‐glucuronosyltransferases (UGTs) drug‐drug interaction chirality |
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