Porter C J, Edwards G A, Charman S A
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Vic. 3052, Australia.
Adv Drug Deliv Rev. 2001 Aug 23;50(1-2):157-71. doi: 10.1016/s0169-409x(01)00153-3.
Subcutaneous (s.c.) administration continues to be the main route for the delivery of protein drugs due to their poor bioavailability by most non-parenteral routes. While small drug molecules are rapidly and extensively absorbed after s.c. injection, the systemic bioavailability of protein drugs is often incomplete and variable. Given the widespread use of the s.c. route for protein drugs, surprisingly little is known about the factors that govern the rate and extent of protein absorption from the interstitial space and the role of the lymphatic system in the transport of these molecules to the systemic circulation. The few studies that have directly addressed the role of lymphatic transport in protein bioavailability are complicated by the use of methods and models that vary widely. In this review we will evaluate the available literature describing the lymphatic transport of proteins after s.c. injection and more specifically, address the impact of experimental variation (e.g. site of cannulation, animal model, anesthesia) on the interpretation of the data obtained. We will also describe in some detail the sheep model currently in use in our laboratory, which allows both estimation of the extent of uptake of protein drugs into the lymphatics draining the injection site, and quantification of the contribution of lymphatic transport to the absolute bioavailability.
由于大多数非肠道给药途径的生物利用度较差，皮下（s.c.）给药仍然是蛋白质药物递送的主要途径。虽然小分子药物在皮下注射后能迅速且广泛地被吸收，但蛋白质药物的全身生物利用度往往不完全且存在差异。鉴于皮下途径在蛋白质药物中的广泛应用，令人惊讶的是，对于控制蛋白质从间质空间吸收的速率和程度的因素以及淋巴系统在这些分子向全身循环运输中的作用，我们了解得很少。少数直接探讨淋巴转运在蛋白质生物利用度中作用的研究，因所使用的方法和模型差异很大而变得复杂。在这篇综述中，我们将评估描述皮下注射后蛋白质淋巴转运的现有文献，更具体地说，探讨实验差异（如插管部位、动物模型、麻醉）对所获数据解释的影响。我们还将详细描述目前我们实验室正在使用的绵羊模型，该模型既能估计蛋白质药物进入注射部位引流淋巴管的摄取程度，又能量化淋巴转运对绝对生物利用度的贡献。
