Identifying the Dominant Contribution of Human Cytochrome P450 2J2 to the Metabolism of Rivaroxaban, an Oral Anticoagulant

Zhao, Tingting; Chen, Yanwei; Wang, Dalong; Wang, Liyan; Dong, Peipei; Zhao, Shuyuan; Wang, Changyuan; Meng, Qiang; Sun, Huijun; Liu, Kexin; Wu, Jingjing

doi:10.1007/s10557-020-07129-z

Cited by 23 publications

(30 citation statements)

References 39 publications

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“…The inhibitory effect of the TKIs on the metabolism of rivaroxaban in recombined P450 isoforms and pooled human liver microsomes were compared by quantifiably detecting the production of the major metabolite using HPLC. The detection and quantitative analysis were achieved by HPLC, as described in our previous study (Zhao et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

“…The concentration of HLM, CYP2J2 and CYP3A4 was 0.3, 0.4 and 0.6 mg•mL -1 . The selection of the rivaroxaban concentration depended on the K m values of the kinetic studies (22.81, 19.37 and 46.98 μM for HLM, CYP2J2 and CYP3A4, respectively) (Zhao et al, 2021). The concentration of CYP3A4 (0.6 mg•mL -1 ) was selected to correspond with the lowest detected concentration of M1.…”

Section: Enzyme Inhibition Assaysmentioning

confidence: 99%

“…The concentration of CYP3A4 (0.6 mg•mL -1 ) was selected to correspond with the lowest detected concentration of M1. The detailed method can be found in our previous publication (Zhao et al, 2021).…”

Section: Enzyme Inhibition Assaysmentioning

confidence: 99%

“…The degradation rates (K deg ) of CYP2J2 and CYP3A4 were 0.00026 and 0.00032 min -1 , respectively (Cheong et al, 2017), where I represented the in vivo concentration of inhibitors in healthy and solid tumour patients. Additionally, the fraction of rivaroxaban metabolised by CYP2J2 or CYP3A4 was input from our previous study (Zhao et al, 2021), which were 0.95 for CYP2J2 and 0.025 for CYP3A4.…”

Section: Quantitative Prediction Of Ddi Riskmentioning

confidence: 99%

“…Although in vivo pharmacokinetic data are stable, bleeding is still a risk factor that should be considered for medication safety. Our previous studies have shown CYP2J2 and CYP3A4 to be the major isoforms involved in the metabolic process of rivaroxaban, and importantly CYP2J2 showed˜39-fold higher catalytic efficiency than CYP3A4 (Zhao et al, 2021). CYP3A4 is always considered as the enzyme which resulted in drug-drug interactions (DDIs), however, CYP2J2 is always ignored due to its lower abundance in the liver.…”

Section: Introductionmentioning

confidence: 99%

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A combined medication safety assessment of rivaroxaban with Tyrosine Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4

Zhao¹,

Li²,

Chen³

et al. 2021

Preprint

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Enzyme Inhibition Assaysmentioning

confidence: 99%

Section: Enzyme Inhibition Assaysmentioning

confidence: 99%

Section: Quantitative Prediction Of Ddi Riskmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A combined medication safety assessment of rivaroxaban with Tyrosine Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4

Zhao¹,

Li²,

Chen³

et al. 2021

Preprint

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Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non‐valvular atrial fibrillation

Zhang

Qin

et al. 2022

Biopharm & Drug Disp

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Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study.Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (C max /D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban C max /D than non-carriers. Logistic regression showed that rivaroxaban C max /D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban C max /Dose and the incidence of hemorrhage events significantly.

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Molecular Docking and Dynamics Simulations of Ammi visnaga L. Constituents as Antimelanogenic, Anti‐Inflammatory and Anticoagulant Agents

Çatıkkaş,

Karacan

2023

Chemistry & Biodiversity

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In this study, anti‐melanogenic, anti‐inflammatory and anti‐coagulant potentials of eighteen selected constituents of Ammi visnaga L. were investigated by Induced Fit Docking (IFD) and molecular dynamic simulation with Schrödinger software. The binding free energies of the selected natural compounds were computed by means of ΔG MM‐GBSA studies. Anti‐melanogetic activity of the constituent against agaricus bisporus tyrosinase, Priestia megaterium tyrosinase and Homo sapiens tyrosinase were evaluated. The result showed that apiumetin had more negative binding free energy against three tyrosinase enzymes than cognate ligands, tropolone and kojic acid. Docking analysis was also performed to predict the constituents with anti‐inflammatory activity against human Tumor necrosis factor, Cyclooxygenase‐2, Prostaglandin D2 11‐ketoreductase AKR1C3 and Prostaglandin reductase PTGR2. The results showed that pyranocoumarins (visnadin, dihydrosamidin, samidin) have more negative binding free energy against Cyclooxygenase‐2 and Prostaglandin D2 11‐ketoreductase receptors than cognate drugs, rofecoxib and indomethacin. In addition, docking analysis shows that pyranocoumarins, apiumetin and cimifugin have more negative binding free energy against Vitamin K epoxide reductase than S‐warfarin drug, predicting that they have anticoagulant activity. Furthermore, the constituents and their cognate drugs were subjected to 100 ns MD Simulation to predict their stability at the active sites of the enzymes.

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Identifying the Dominant Contribution of Human Cytochrome P450 2J2 to the Metabolism of Rivaroxaban, an Oral Anticoagulant

Cited by 23 publications

References 39 publications

A combined medication safety assessment of rivaroxaban with Tyrosine Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4

A combined medication safety assessment of rivaroxaban with Tyrosine Kinase Inhibitors for cancer patients: focusing on CYP2J2 and CYP3A4

Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non‐valvular atrial fibrillation

Molecular Docking and Dynamics Simulations of Ammi visnaga L. Constituents as Antimelanogenic, Anti‐Inflammatory and Anticoagulant Agents

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