Abstract:
PURPOSE: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 is 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.
journal_name
Cardiovasc Drugs Therjournal_title
Cardiovascular drugs and therapyauthors
Zhao T,Chen Y,Wang D,Wang L,Dong P,Zhao S,Wang C,Meng Q,Sun H,Liu K,Wu Jdoi
10.1007/s10557-020-07129-zsubject
Has Abstractpub_date
2021-01-07 00:00:00eissn
0920-3206issn
1573-7241pii
10.1007/s10557-020-07129-zpub_type
杂志文章abstract:OBJECTIVE:Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Ai...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-008-6117-8
更新日期:2008-10-01 00:00:00
abstract::The pathogenetic theories and treatment of Raynaud's phenomenon are reviewed. In primary Raynaud's disease, most evidence supports a local defect at the digital artery level, with vasoconstriction or vasospasm of the digital arteries inducing the color changes. Normal sympathetic activity, low transmural arterial dist...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF00053426
更新日期:1990-01-01 00:00:00
abstract:PURPOSE:Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. Azelnidipine is a novel dihydropyridine calcium channel blocker. Several studies have demonstrated that some dihydropyridine calcium channel blockers have antioxidant effects. We evaluated the antioxidant effects of azelnid...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-007-6008-4
更新日期:2007-02-01 00:00:00
abstract:BACKGROUND:Clinical guidelines recommend peri-cardioversion anticoagulation in patients with atrial fibrillation (AF). We performed a systematic review and meta-analysis to compare the safety and efficacy of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with AF undergoing cardiovers...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,meta分析
doi:10.1007/s10557-019-06869-x
更新日期:2019-06-01 00:00:00
abstract::To further evaluate the significance of p38 MAPK as trigger or mediator in ischaemic preconditioning, anisomycin and SB 203580 were used to manipulate its activation status. Special attention was given to the concentration of the drugs and protocols used. The isolated perfused rat heart, subjected to either 25 min glo...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1026116022552
更新日期:2003-05-01 00:00:00
abstract:INTRODUCTION:Surrogate markers represent a significant contribution to early diagnosis, longitudinal prognoses, and outcome prediction in cases of hypertension. They often enable detection of disease and disease potential when the disease is still subclinical and are useful noninvasive tools for designing and evaluatin...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/s10557-009-6177-4
更新日期:2009-08-01 00:00:00
abstract::True positive inotropy of enoximone is hard to prove clinically. It could increase the risk of myocardial ischemia when used in coronary artery disease (CAD). The analysis of the end-systolic pressure-volume relationship (ESPVR) as a load-independent parameter of the contractile left ventricular function (LVF) allows ...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF02018269
更新日期:1990-10-01 00:00:00
abstract::The original version of this article unfortunately contained a mistake. There was a typo in the second sentence of the paragraph under the section Was the Dose of Drugs Fair?; "320 mg twice a day" should read "160mg twice a day". The corrected paragraph is shown below. ...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,已发布勘误
doi:10.1007/s10557-018-6834-6
更新日期:2018-12-01 00:00:00
abstract::Antihypertensive drugs may lower blood pressure through very different mechanisms, initially as well as during chronic use. This article is a review of the immediate hemodynamic changes induced by a beta blocker (visacor), an alpha-receptor blocker (doxazosin), two calcium antagonists (tiapamil and nisoldipine), an an...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF01856510
更新日期:1990-08-01 00:00:00
abstract:PURPOSE:Dofetilide is class III antiarrhythmic agent which prolongs cardiac action potential duration because of selective inhibition of I (Kr), the rapid component of the delayed rectifier K(+) current. Although clinical studies reported on proarrhythmic risk associated with dofetilide treatment, the contributing elec...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-012-6405-1
更新日期:2012-12-01 00:00:00
abstract::Encainide is a class 1C antiarrhythmic agent that is indicated for the treatment of life-threatening arrhythmias, such as sustained ventricular tachycardia. Furthermore, encainide possesses a moderate degree of antiserotonin activity, which was quantitated in this present study by determining displacement of [3H]spipe...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF03029752
更新日期:1991-08-01 00:00:00
abstract:PURPOSE:The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. METHODS:The Novel Cardiovascular Therapeutics S...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/s10557-017-6739-9
更新日期:2017-08-01 00:00:00
abstract::ATP generates nitric oxide (NO) via activation of P2y receptors, and is degraded to adenosine. This study was undertaken to examine whether ATP causes coronary hyperemic flow via purinoceptors-, NO- and adenosine-dependent mechanisms, and attenuates the severity of contractile and metabolic dysfunction in the ischemic...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1007899822136
更新日期:1999-09-01 00:00:00
abstract:PURPOSE:The glucagon-like peptide-1 (GLP-1) has been shown to exert cardioprotective effects in animals and patients. This study tests the hypothesis that preservation of GLP-1 by the GLP-1 receptor agonist liraglutide or the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is associated with a reduction of angiote...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-015-6592-7
更新日期:2015-06-01 00:00:00
abstract:BACKGROUND:The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) is currently expanding to cardiovascular risk reduction in non-diabetic subjects, but renal (side-)effects are less well studied in this setting. METHODS:Male non-diabetic Sprague Dawley rats underwent permanent coronary artery ligation to induc...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-020-06954-6
更新日期:2020-06-01 00:00:00
abstract::The effects of short- and long-term administration of nifedipine on serum lipids, lipoproteins, and apolipoproteins (apo) were studied. Administration of nifedipine capsule for 4 months significantly decreased triglycerides and increased the HDL2 cholesterol and the HDL2/HDL3 cholesterol ratio. No significant changes ...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章
doi:10.1007/BF02018313
更新日期:1990-08-01 00:00:00
abstract::Amlodipine increases NO levels in coronary vessels and aorta via bradykinin-dependent mechanisms in vitro. We have previously reported that a long-acting Ca channel blocker, benidipine, increases cardiac NO levels in ischemic canine hearts, suggesting that benidipine may also protect against ischemia and reperfusion i...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1011964222712
更新日期:2001-01-01 00:00:00
abstract::The present study was designed to evaluate the effects of oral verapamil and normal diet on regression of atherosclerotic plaque in cholesterol fed rabbits. Forty-three rabbits were separated into 6 groups and studied for 24 weeks. All groups had a cholesterol diet for the first 12 weeks. Group I was then sacrificed a...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF02125835
更新日期:1987-01-01 00:00:00
abstract:PURPOSE:Platelets are essential for primary hemostasis; however, platelet activation also plays an important proinflammatory role. Inflammation promotes the development of cardiac fibrosis and heart failure induced by hypertension. In this study, we aimed to determine whether inhibiting platelet activation using clopid...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-013-6471-z
更新日期:2013-12-01 00:00:00
abstract::Pulmonary arterial hypertension (PAH) is a group of diseases characterized by a progressive increase of pulmonary vascular resistance (PVR), initially due to abnormal pulmonary vasoconstriction in response to endothelial injury. Recent studies have here confirmed the prominent role of endothelin (ET)-1 in vasoconstric...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/s10557-015-6605-6
更新日期:2015-01-01 00:00:00
abstract::Elgodipine is a new second-generation dihydropyridine calcium antagonist. Its hemodynamic and antiischemic properties were evaluated in a single-blind, placebo-controlled trial in 22 males with chronic stable angina. Coronary artery disease was angiographically confirmed. Measurements were performed with a Swan-Ganz t...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章
doi:10.1007/BF00878092
更新日期:1995-08-01 00:00:00
abstract::Concentrations of the circulating hepatocyte growth factor (HGF) increase in the very early phase of acute myocardial infarction, and are a marker of arterial thrombosis. A recently developed, highly sensitive HGF assay can detect the early stages of arterial thrombosis in patients with unstable angina pectoris, acute...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1023/B:CARD.0000041252.33870.74
更新日期:2004-07-01 00:00:00
abstract::A survey of the pharmacokinetic properties of the three prototypical calcium antagonist agents shows that they have in common a very high rate of hepatic first-pass metabolism with, in the case of verapamil and diltiazem, the formation of an active metabolite that affects the dose during chronic therapy. Therefore, th...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章,评审
doi:10.1007/BF01865507
更新日期:1989-08-01 00:00:00
abstract::The purpose of this study was to examine the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the elastic properties of the aorta. A standard diuretic antihypertensive drug, hydrochlorothiazide, served for comparisons. Increased aortic stiffness leads to a reduction of the buffering windkesse...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF00051130
更新日期:1996-03-01 00:00:00
abstract::The vasorelaxant activity of the omega-3 fatty acids--docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids--in comparison with other known vasodilators--sodium nitroprusside, nitroglycerin, papaverine, and D600--were studied in the isolated rat aorta. The relaxant responses of these vasodilators and fatty acids at c...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF00052562
更新日期:1992-12-01 00:00:00
abstract::There is considerable evidence implicating a key role for p38 mitogen-activated protein kinase (MAPK) in ischemic and pharmacological preconditioning against myocardial infarction. However, there have been few, if any, studies examining the role of p38 MAPK in the protection of stunned myocardium. The purpose of this ...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-004-6220-4
更新日期:2004-11-01 00:00:00
abstract::In patients with hypertension persisting on combined diuretic and beta-blocker therapy, the effects of an additional 9-week therapy with a calcium antagonist (nifedipine) versus a classical arterial vasodilator (hydralazine) were compared for changes in blood pressure (BP), plasma catecholamines (n = 15), and left ven...
journal_title:Cardiovascular drugs and therapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/BF01857760
更新日期:1990-04-01 00:00:00
abstract::Intravenous amiodarone has been found useful in the emergent management of life-threatening arrhythmias. Experimental studies have shown that its electrophysiologic effects are proportional to its myocardial concentration. However, early after its intravenous administration, the extent of the concentration of amiodaro...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1023/a:1007756411790
更新日期:1999-05-01 00:00:00
abstract::To characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invasive hemodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with mode...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/BF00054205
更新日期:1988-12-01 00:00:00
abstract:PURPOSE:Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with hea...
journal_title:Cardiovascular drugs and therapy
pub_type: 杂志文章
doi:10.1007/s10557-019-06909-6
更新日期:2019-12-01 00:00:00