新凝血因子Ⅹa抑制剂Bg115-2的抗血栓作用及药代动力学

目的 探讨Bg115-2的抗血栓功效和初步药代动力学性质。方法 试剂盒测定小鼠半体内凝血酶原时间（PT）和活化部分凝血活酶时间（APTT）；采用小鼠下腔静脉结扎模型评价对静脉血栓的作用；采用尾尖测定出血时间法；用FⅩa活性测定Bg115-2的血药浓度。结果 sc给予Bg115-2 0.19~3.0 mg·kg^-1可明显地、剂量依赖地延长PT (P<0.05, P<0.01)和APTT (P<0.01)；Bg115-2 0.75~3.0 mg·kg^-1可显著地减轻血栓质量，其抑制50%血栓形成的剂量（ID₅₀）为0.19 mg·kg^-1；ig给予Bg115-2 1.5~6.0 mg·kg^-1也明显地减轻血栓质量(P<0.01)。Bg115-2的出血反应与那曲帕林钙相似，有较高的出血风险效益比，ED₂/ID₅₀为26.8。另外单次sc给予Bg115-2 3.0 mg·kg^-1显示出二室模型的药代动力学特点，t_1/2为（6.18±1.45)h, c_max为(5.20±0.66)mg·L^-1, AUC为(43.75±8.20)mg·L^-1·h。结论 Bg115-2为一注射和口服均可的、强效的静脉血栓形成抑制剂，出血不良作用较轻。它具有较长的半衰期和二室模型的分布特征。

Anti-thrombotic effect and pharmacokinetics of a novel factor Xa inhibitor Bg115-2 in mice

OBJECTIVE To evaluate antithrombotic efficacy and preliminary pharmacokinetics of Bg115-2.METHODS Prothrombin time(PT) and activated partial thromboplastin time(APTT) in vitro were determined using assay kits,respectively.The effect on venous thrombosis was evaluated with the model of inferior sinus venous thrombosis in mice.Bleeding reaction was measured by tail bleeding time test.Preliminary pharmacokinetic study was conducted using F Xa activity assay.RESULTS Bg115-2(sc) 0.75-3.0 mg·kg-1 prolonged PT(P<0.05,P<0.01) and APTT(P<0.01) dose-dependently.In the inferior sinus venous thrombosis model,Bg115-2 0.19-3.0 mg·kg-1 significantly reduced thrombus mass with ID50 of 0.19 mg·kg-1.Interestingly,Bg115-2(ig) 1.5-6.0 mg·kg-1 also significantly reduced venous thrombus mass(P<0.01).Bg115-2 was similar to nadroparin calcium in bleeding reaction,and ED2/ID50 reached up to 26.8.Furthermore,Bg115-2 3.0 mg·kg-1 displayed a pharmacokinetic character with a two-compartment model.t1/2,cmax and AUC were(6.18±1.45)h,(5.20±0.66)mg·L-1 and(43.75±8.20)mg·L-1·h,respectively.CONCLUSION Bg115-2 is a potent and oral effective inhibitor of venous thrombosis in mice with slight bleeding side-effect.It has longer t1/2 and the distribution character of a two-compartment model.