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目的考察重组水蛭素跨膜转运的基本特点和影响因素,对转运的机制进行初步的探讨,为重组水蛭素肺部给药的体内评价打下理论基础。方法将蟾蜍肺泡膜作为肺液上皮体外模型,装在水平扩散池上,向给药池中加入荧光标记的重组水蛭素(FTTC-rHV2),在不同的温度、不同的给药池初始浓度、不同的转运方向的条件下测定表观渗透系数,同时考察给药池溶液中高渗透压、酸性pH、加入渗透促进剂或者代谢抑制剂时的转运情况。同时监测膜电阻的变化。结果FTTC-rHV2的表观渗透系数具有浓度非依赖性、温度非依赖性和方向非依赖性。酸性pH环境、高渗透压和吸收促进剂使表现渗透系数明显增加,而代谢抑制剂对袁观渗透系数没有明显的影响。3h内膜电阻没有明显的变化,说明膜的完整性得以保持。结论重组水蛭素经蟾蜍肺泡膜的转运是一个非能量依赖、非载体依赖的被动扩散过程。
Objective To investigate the basic characteristics and influencing factors of transmembrane transport of recombinant hirudin, and to explore the mechanism of transport, and lay a theoretical foundation for the in vivo evaluation of recombinant hirudin for pulmonary administration. Methods The sputum alveolar membrane was used as an in vitro model of pulmonary epithelium and mounted on a horizontal diffusion cell. Fluorescence labeled recombinant hirudin (FTTC-rHV2) was added to the dosing tank. The initial concentration and the different concentrations were different at different temperatures. The apparent permeability coefficient was measured under the conditions of the transport direction, and the transport conditions of the high osmotic pressure, the acidic pH, the addition of the permeation enhancer or the metabolic inhibitor in the solution of the dosing tank were examined. Measure changes in membrane resistance at the same time. Results The apparent permeability coefficient of FTTC-rHV2 was concentration-independent, temperature-independent and direction-independent. Acidic pH environment, high osmotic pressure and absorption enhancer increase the apparent permeability coefficient, while metabolic inhibitors have no significant effect on Yuanguan permeability coefficient. There was no significant change in intima resistance at 3 h, indicating that the integrity of the membrane was maintained. Conclusion Recombinant hirudin translocation through the alveolar membrane is a non-energy dependent, non-vector dependent, passive diffusion process.