Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats
Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats
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DOI：
10.1080/13880209.2020.1785510
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发表时间：
2020-01-01
影响因子：
3.8
通讯作者：
Yang, Jiefu
中科院分区：
文献类型：
--
作者：
Chong, Jia;Chen, Hao;Yang, Jiefu
利伐沙班和替格瑞洛是治疗心房颤动和急性冠状动脉综合征的两种常用药物。然而，它们之间的相互作用仍然是未知的。目的探讨替格瑞洛对利伐沙班大鼠体内和体外药动学的影响。材料与方法建立了灵敏、可靠的超高效液相色谱-质谱联用法测定大鼠血浆中利伐沙班的含量。10只Sprague-Dawley大鼠随机分为替格瑞洛预处理组（10 mg/kg/d，连用14 d）和对照组。采用超高效液相色谱-质谱联用（UPLC-MS/MS）法研究口服利伐沙班（10 mg/kg，单剂量）加替格瑞洛或不加替格瑞洛预处理的药代动力学。此外，我们还利用Sprague-Dawley大鼠肝微粒体体外研究了这两种药物之间的药物相互作用。结果替格瑞洛预处理后，利伐沙班的c (max)（221.34 +/- 53.33vs.691.18 +/- 238.31 ng/mL）和AUC((0-t) （1060.97 +/- 291.21vs.3483.03 +/- 753.83 mu g中心点h/L）显著升高（p < 0.05）。替格瑞洛预处理后，利伐沙班的MRT从4.41 +/- 0.79增加到5.97 +/- 1.11 h，内在清除率从9.93 +/- 2.55下降到2.89 +/- 0.63 L/h/kg （p均< 0.05）。酶动力学研究表明，替格瑞洛降低了利伐沙班代谢清除率，IC（50）值为14.04 mu mol/L。结论体外实验结果表明替格瑞洛与利伐沙班在大鼠体内存在药物相互作用。需要进一步的研究来验证类似的相互作用是否真正适用于人类，以及这些相互作用是否具有临床意义。
Context Rivaroxaban and ticagrelor are two common drugs for the treatment of atrial fibrillation and acute coronary syndrome. However, the drug-drug interaction between them is still unknown. Objective To investigate the effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats bothin vivoandin vitro. Materials and methods A sensitive and reliable UPLC-MS/MS method was developed for the determination of rivaroxaban in rat plasma. Ten Sprague-Dawley rats were randomly divided into ticagrelor pre-treated group (10 mg/kg/day for 14 days) and control group. The pharmacokinetics of orally administered rivaroxaban (10 mg/kg, single dose) with or without ticagrelor pre-treatment was investigated with developed UPLC-MS/MS method. Additionally, Sprague-Dawley rat liver microsomes were also used to investigate the drug-drug interaction between these two drugsin vitro. Results TheC(max)(221.34 +/- 53.33vs.691.18 +/- 238.31 ng/mL) and the AUC((0-t))(1060.97 +/- 291.21vs.3483.03 +/- 753.83 mu g center dot h/L) of rivaroxaban increased significantly (p < 0.05) with ticagrelor pre-treatment. The MRT((0-infinity))of rivaroxaban increased from 4.41 +/- 0.79 to 5.97 +/- 1.11 h, while the intrinsic clearance decreased from 9.93 +/- 2.55 to 2.89 +/- 0.63 L/h/kg (bothp < 0.05) after pre-treated with ticagrelor. Enzyme kinetic study indicated that ticagrelor decreased rivaroxaban metabolic clearance with the IC(50)value of 14.04 mu mol/L. Conclusions Ourin vivoandin vitroresults demonstrated that there is a drug-drug interaction between ticagrelor and rivaroxaban in rats. Further studies need to be carried out to verify whether similar interactions truly apply in humans and whether these interactions have clinical significance.