Background and Purpose: Rivaroxaban as an oral anticoagulant is widely used for the prevention and treatment of thromboembolic disease. Previous studies revealed cytochrome P450 (CYP)–mediated metabolism of rivaroxaban mainly involves CYP2J2 and CYP3A4. Imatinib, sunitinib and gefitinib are three tyrosine kinase inhibitors (TKIs) that are extensively applied for anti-cancer therapy. Statistical research has shown cancer patients are at approximately 4-7–fold higher risk of vein thromboembolism than normal patients. Therefore, rivaroxaban and TKIs have a profound combination foundation. This study aimed to comprehensively assess the combination safety of rivaroxaban with TKIs in vitro. Experimental Approach: First, the inhibitory activity of the three TKIs was screened. Second, to comprehensively evaluate their inhibitory potential, the reversible and mechanism-dependent inhibitory kinetic constants of three TKIs on CYP2J2 and CYP3A4 were determined. Docking simulation was used to explore the molecular mechanism. Finally, drug-drug interaction (DDI) risks of the combination were assessed using pharmacokinetic data of cancer patients. Key Results: Imatinib and gefitinib exerted significant reversible inhibition of both CYP2J2 and CYP3A4, while sunitinib only showed reversible inhibition of CYP3A4, not CYP2J2. Three TKIs also showed time-dependent inactivation of CYP3A4 and slightly on CYP2J2. Notably, sunitinib had a significantly stronger inactivation effect on CYP3A4 than the other TKIs, with a 4.14-fold IC50 shift. Imatinib was predicted to cause a 114–244% increase in rivaroxaban exposure. Conclusion and Implication: Imatinib showed the strongest inhibition, which was predicted to have a moderate DDI risk. These results provide evidence for medication guidance when combining rivaroxaban with TKIs.

Background and purpose: Cancer patients are always complicated with vein thromboembolism, thus the combination of anticoagulants with anti-cancer drugs has profound foundations. This study aimed to assess the safety of rivaroxaban comminating with three tyrosine kinase inhibitors (TKIs) in cancer patients. Experimental Approach: The inhibition of three TKIs on CYP2J2- and CYP3A4-mediated rivaroxaban metabolism was first screened and then reversible and mechanism-dependent inhibitory kinetic constants were determined. Molecular docking was conducted to reveal the interactions between TKIs and CYP2J2 and CYP3A4. Finally, pharmacokinetic parameters of cancer patients were used to assess the safety. Key Results: Imatinib and gefitinib significantly reversibly inhibited CYP2J2- and CYP3A4-mediated rivaroxaban metabolism, while sunitinib only showed reversible inhibition of CYP3A4, not CYP2J2. Three TKIs also showed time-dependent inactivation of CYP3A4. Notably, sunitinib had the strongest inactivation effect on CYP3A4 than the other TKIs with a 4.00-fold IC50 shift, however, a slight effect on CYP2J2. Docking simulations revealed the relation of inhibitory activity to ChemScore. Additionally, drug-drug interaction risks of combinations were assessed using pharmacokinetic data of cancer patients. Imatinib, which showed the strongest inhibition, was predicted to cause a 114–244% increase in rivaroxaban exposure. Conclusion and Implications: Imatinib was predicted to have a moderate DDI risk when was combined with rivaroxaban. These results provide evidence for medication guidance when combining rivaroxaban with TKIs for cancer patients, and also give new insight for the DDI assessment involving rivaroxaban.

Aim Rivaroxaban, an oral anticoagulant, undergoes the metabolism mediated by human cytochrome P450 (CYP). The present study is to quantitatively analyze and compare the contributions of multiple CYPs in the metabolism of rivaroxaban to provide new information for medication safety. Methods The metabolic stability of rivaroxaban in the presence of human liver microsomes (HLMs) and recombinant CYPs was systematically evaluated to estimate the participation of various CYP isoforms. Furthermore, the catalytic efficiency of CYP isoforms was compared via metabolic kinetic studies of rivaroxaban with recombinant CYP isoenzymes, as well as via CYP-specific inhibitory studies. Additionally, docking simulations were used to illustrate molecular interactions. Results Multiple CYP isoforms were involved in the hydroxylation of rivaroxaban, with decreasing catalytic rates as follows: CYP2J2 > 3A4 > 2D6 > 4F3 > 1A1 > 3A5 > 3A7 > 2A6 > 2E1 > 2C9 > 2C19. Among the CYPs, 2J2, 3A4, 2D6 and 4F3 were the four major isoforms responsible for rivaroxaban metabolism. Notably, the intrinsic clearance of rivaroxaban catalyzed by CYP2J2 was nearly 39-, 64- and 100-fold that catalyzed by CYP3A4, 2D6 and 4F3, respectively. In addition, rivaroxaban hydroxylation was inhibited by 41.1% in the presence of the CYP2J2-specific inhibitor danazol, which was comparable to the inhibition rate of 43.3% by the CYP3A-specific inhibitor ketoconazole in mixed HLMs. Furthermore, molecular simulations showed that rivaroxaban principally bound to CYP2J2 by π-alkyl bonds, carbon-hydrogen bonds and alkyl interactions. Conclusion CYP2J2 dominated the hydroxylation of rivaroxaban, which may provide new insight into clinical drug interactions involving rivaroxaban.