蛋白质与多肽药物口服药效学动物评价模型的构建

Oral delivery of protein and peptide drugs has been one of most intensively studied research subject in the field of biological pharmacy in the recent years. The oral drugs absorption will experience the hepatic and intestinal first-pass effects which reduce the drug bioavailability to affect the clinical efficacy. To overcome the absorption barriers present in the gastrointestinal tract and increase the intestinal permeation of protein and peptide drugs are attracting a close attention of the world now. However, Taking blood concentration in systemic circulation as assessment index has great limitations. When protein and peptide drugs are given orally, before the drugs entering the systemic circulation, most of the doses will be stored, bind or metabolized by liver as it must enter the liver by way of hepatic portal vein. At the same time, liver is also the target organ of some protein and peptide drugs. When the amount of these drugs reaching the liver, hepatic extraction was significantly great. So just taking blood concentration in systemic circulation as assessment index is one-sided. Because both liver and small intestine can affect the oral absorption of protein and peptide drugs. So we propose a new animal model to evaluate the pharmacodynamics of oral protein and peptide drugs. We establish rat models with jugular vein cannulation, portal vein cannulation or intestinal cannulation under consciousness. Then we can multiple dose through the duodenum and portal vein and collect the blood sample several times from the same animal with consciousness in free condition. Then the blood concentration of the rats treated with oral delivery system in hepatic portal vein, liver and systemic circulation will be analyzed to evaluate the oral delivery system. And if the drug target liver, disease related indexes in liver will be also studied. Then the relate mathematics models will also be built in order to quantitatibely distinguish the intestine and liver which affect the oral bioavailability of protein and peptide drugs. According to the above, we hope those discussion here will be provide some useful reference for the oral delivery of protein and peptide drugs.

蛋白质与多肽药物口服制剂的研发是生物制药领域的热点和难点，肝肠首过效应导致其口服生物利用度很低。目前研究思路主要是如何突破肠屏障，促进药物的小肠吸收，并通过检测体循环中相关指标变化评价口服疗效。这种研究方式有一定的局限性，口服给药时，药物经小肠吸收后必须通过肝门静脉进入肝脏，大部分药物在这里被蛋白结合或储存或被代谢，导致进入体循环的药量远少于吸收的量；同时，部分药物的主要作用位点在肝脏，肝脏对该类型药物的提取率较高，因此以体循环中相关指标（特别是血药浓度）变化来评价口服制剂是否有效比较片面。鉴于肝脏和小肠在药物口服吸收中的重要地位，我们改进了动物评价模型，采用了十二指肠、肝门静脉和颈静脉插管技术，在动物清醒状态下进行给药和血液采样，分析并建立相应的数学模型，定量区分肠屏障与肝代谢对蛋白质与多肽药物口服生物利用度的影响，为合理评价蛋白质与多肽药物口服给药系统提供坚实的技术支持与理论指导。

蛋白质与多肽药物口服制剂的研发是生物制药领域的热点和难点，为了能够系统的对口服制剂进行药效学评价，我们提出了新的药效学评价思路，对口服制剂的评价分为小肠吸收屏障和肝脏首过效应，找出口服制剂的主要限速步骤。（1）建立了十二指肠和肝门静脉插管大鼠、十二指肠和颈静脉插管大鼠、肝门静脉和颈静脉插管大鼠、股静脉和颈静脉插管大鼠这四种动物模型，通过这四种动物插管模型系统的研究口服制剂的小肠吸收，肝脏首过效应以及肝脏代谢等。（2）利用建立的插管动物模型，对肝靶向药物胰岛素和非肝靶向药物鲑降钙素进行药效学评价，并且找到了肝靶向药物胰岛素的主要屏障为小肠吸收，而非肝靶向药物鲑降钙素的主要屏障肝脏首过效应。通过建立的动物模型平台，对口服大分子药物进行大规模的筛选和合理的药效学评价，找到限制其生物效应的主要屏障，从而指导口服制剂的开发，如针对肝靶向药物胰岛素的口服递送系统的研究和非肝靶向药物鲑降钙素克服其肝脏首过效应的研究。