Argatroban is a thrombin inhibitor used as anticoagulant in patients with heparin-induced thrombocytopenia. It is usually administered as an intravenous bolus followed by infusion. Nevertheless, its pharmacokinetics after subcutaneous administration is unknown. The aim of this study was to assess the pharmacokinetics of two different formulations of argatroban in pigs after subcutaneous administration. Antithrombotic activity in plasma was determined by ecarin chromogenic assay. To visualize the formation of crystals, argatroban was administered to rats into the subcutaneous tissue exposed after removing the skin, and the injection site was photographed at different times. After subcutaneous administration of a sorbitol/ethanol formulation of argatroban in pigs was observed a slow absorption phase was followed by long-lasting levels of this inhibitor. C max and AUC(0−24) showed dose-dependent increases, while elimination half-life and t max value did not change significantly with dose. In contrast, saline-dissolved argatroban showed a faster absorption phase followed by a shorter elimination half-life. Argatroban dissolved in sorbitol/ethanol leads to long-lasting plasma levels due to the formation and permanent dissolution of a crystalline depot at the injection place. This represents a simple way to deliver argatroban continuously over an extended period which can be beneficial for prophylaxis or treatment of chronic coagulations disorders.
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机译:Argatroban是一种凝血酶抑制剂,可在肝素诱导的血小板减少症患者中用作抗凝剂。通常以静脉推注方式给药,然后输注。然而,皮下给药后其药代动力学尚不清楚。本研究的目的是评估皮下给药后两种不同制剂argatroban在猪中的药代动力学。通过依卡琳生色测定法测定血浆中的抗血栓形成活性。为了观察晶体的形成,将阿加曲班施用给大鼠,将其去除皮肤后暴露在皮下组织中,并在不同时间拍摄注射部位。观察到猪皮下注射argatroban的山梨糖醇/乙醇制剂后,观察到缓慢的吸收阶段,随后是该抑制剂的持久水平。 C max和AUC(0-24)显示剂量依赖性增加,而消除半衰期和t max值不随剂量显着变化。相比之下,盐水溶解的阿加曲班显示出更快的吸收相,随后具有较短的消除半衰期。溶解在山梨糖醇/乙醇中的Argatroban会导致长期血浆水平升高,这是由于在注射处形成了结晶长效剂并使其永久溶解。这代表了在长时间内连续递送argatroban的简单方法,这对预防或治疗慢性凝血疾病可能是有益的。
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