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目的:对重组水蛭素rHⅧ乳糜微粒(rHⅧ EP)的抗血栓及抗凝效果进行了药效学评价并对其口服给药的吸收机制进行了初步探索。方法:分别采用正常大鼠, 弥散性血管内凝血(DIC)模型大鼠及下腔静脉凝血(IVC)模型大鼠测定rHⅧ乳糜微粒的药效; 将rHⅧ以异硫氰酸荧光黄(FITC)标记后通过Caco-2 单细胞模型和肠外翻模型测定乳糜微粒的初步吸收动力学。结果:体内实验中, rHⅧ EP可延长凝血酶时间(TT), 凝血时间(CT), 并抑制血栓的形成。转运实验证明, rHⅧ在肠的各个部位均有吸收, AP面向BL面的转运速率Papp为(2.68 ± 0.14) ×10-6 cm·s-1, BL到AP的Papp值为(3.02 ± 0.66) ×10-6 cm·s-1, 提示其在肠内的运输方式主要为被动运输。相较于静脉注射方式, rHⅧ乳糜微粒的口服绝对生物利用度为 11.42%。结论:rHⅧ EP具有抗血栓和抗凝作用以及适合的生物利用度。在此基础上, 作者首次提出将rHⅧ制成口服给药的乳糜微粒形式存在良好的开发潜力。
OBJECTIVE: To evaluate the antithrombotic and anticoagulant effects of recombinant hirudin rHⅧ chylomicrons (rHⅧ EP) and to explore its absorption mechanism for oral administration. Methods: The pharmacodynamics of rHVIII chylomicrons were measured in normal rat, diffuse intravascular coagulation (DIC) model rats and IVC rat model. The rHⅧ was treated with FITC The initial absorption kinetics of chylomicrons were determined by Caco-2 single cell model and parenteral model after labeling. Results: In vivo, rHⅧ EP prolonged thrombin time (TT), clotting time (CT), and inhibited thrombus formation. Transport experiments showed that rHⅧ was absorbed in all parts of the intestine, Papp was (2.68 ± 0.14) × 10-6 cm · s-1 for AP and BL, and Papp was (3.02 ± 0.66) for BL. × 10-6 cm · s-1, suggesting that the main mode of transport in the intestine is passive transport. Compared with intravenous injection, oral absolute bioavailability of rHVIII chylomicrons was 11.42%. Conclusion: rHⅧ EP has antithrombotic and anticoagulant effects and suitable bioavailability. On this basis, the authors first proposed that the rHVIII oral administration of chylomicrons form there is a good potential for development.