利伐沙班是一种凝血因子（FXa）直接抑制剂，具有抗凝血作用，常被用于预防和治疗各种静脉栓塞。虽然，现已有诸多关于人体及动物体内的利伐沙班药代动力学相关研究，但利伐沙班对映体立体选择性药代动力学却未有报道。为避免类似“海豹婴儿”的悲剧再次发生，我们有必要对它的立体选择性药代动力学进行全面深入的研究，以确保利伐沙班的疗效及用药安全。本文主要针对立体选择性药代中的大鼠体内手性转化部分对利伐沙班对映体进行了研究，建立并验证了一种高效、快速的UPLC-MS/MS分离分析方法，并研究了灌胃给药24 h后大鼠体内利伐沙班的组织分布。实验结果如下： Chiralpak IC柱可成功分离利伐沙班对映体。色谱及质谱条件为：流动相水:乙腈=10:90，流速0.4 mL/min，柱温25 ℃；电喷雾离子源（ESI）以正离子方式检测，扫描方式：多反应监测（MRM），利伐沙班定量分析母离子与子离子质荷比m/z分别为436.00和144.87，毛细管电压、锥孔电压、碰撞电压分别为3.5 kV、44 V和28 V。方法准确度=94.8~100.5%、精密度RSD≤2%、最低检出限=0.39 ng/mL、最低定量限=1.3 ng/mL，且在2~200 ng/mL的浓度范围内，S-利伐沙班的浓度与其峰面积具有良好的线性关系（r2=0.9959）。由此可见，该方法可有效、灵敏、精准地分离分析利伐沙班对映体。 大鼠分别单次灌胃给药4.0 mg/kg利伐沙班对映体，于吸收相、平衡相和消除相分别取血数次，并用以上方法分离分析血浆中的利伐沙班对映体，所得结果如下：R-构型进入大鼠体内30 min内迅速单向手性转化为S-构型，且S-构型在tmax=2 h时达到最大血药浓度Cmax（1842 ng/mL），但R-构型血药浓度始终接近于零；S-构型在大鼠体内不发生手性转化，当tmax=1 h时S-构型达到最大血药浓度Cmax（327.2 ng/mL）。 大鼠单次灌胃给药4.0 mg/kg利伐沙班24 h后，组织分布特点为：肺中浓度最高，279.7 ng/mL，其次为肝脏，228.044 ng/mL，肾脏中的含量最低，179.284 ng/mL。

Rivaroxaban is a selectively direct inhibitor of clotting factor (Factor Xa). Because of its anticoagulant effect, it is widely used for the prophylaxis and treatment of venous thromboembolism. There are many researches about pharmacokinetics of rivaroxaban, but few reports about the stereoselective pharmacokinetics of rivaroxaban enantiomers. Therefore, it is necessary to further study it to ensure not only the efficacy but also the safety of rivaroxaban for avoiding the tragedy of the thalidomide event. This article is aim at investigating the chiral inversion part of stereoselective pharmacokinetics of rivaroxaban enantiomers in rat. Meanwhile, we also developed and validated an efficient and rapid UPLC-MS/MS method to separate and analysis rivaroxaban enantiomers. At end of this research, the rat tissue distribution of rivaroxaban was also investigated by an oral administration after 24 h. The results of the experiments are as follow: Rivaroxaban enantiomers were successfully separated by Chiralpak IC column, and the optimized conditions of chromatogram and mass sprctrum were obtained: H2O-acetonitrile=10:90 was used as mobile phase at 0.4 mL/min flow rate, the column temperature maintained at 25 ℃. The detection was performed by positive electrospray ionization (ESI) with multiple reaction monitoring (MRM) transitions of m/z 436.00>144.87 for rivaroxaban enantiomers. The capillary voltage, cone voltage and collision energy were 3.5 kV, 44 V and 28 V respectively. The limit of detection (LOD) and limit of quantification (LOQ) were 0.39 and 1.3 ng/mL, the accuracy was between 94.8% and 100.5%, the precision RSD was below 2%, and there was a excellent linearity and correlation coefficient (r2=0.9959) between the peak area and the concentration of S-rivaroxaban which ranged from 2 ng/mL to 200 ng/mL. These results indicated that this method is effective, sensitive and accurate for separating and analyzing rivaroxaban enantiomers. Respectively drawing rat blood within absorption phase, balance phase and elimination phase after a single oral administration with 4.0 mg/kg R-rivaroxaban, and analyzing rivaroxaban enantiomers in blood were able to get those results as follows: R-rivaroxaban was rapidly and mostly unidirectional biotransformed to S-rivaroxaban within 30 min, and the plasma concentration of S-enantiomer reached the maximum value (Cmax=1842 ng/mL) at 2 h (tmax) after administration, however, in the whole process, the plasma concentration of R-rivaroxaban almost closed to zero. In S-rivaroxaban group, S-enantiomer could not biotransformate to R-enantiomer, and the Cmax of S-rivaroxaban (327.2 ng/mL) reached at tmax =1 h. After a single oral administration 4.0 mg/kg rivaroxaban 24 h to rats, the order of rivaroxaban content in different tissues was: lung (279.7 ng/mL)> liver (228.044 ng/mL)> kidney (179.284 ng/mL).