Lymphatic transport of proteins after s.c. injection: implications of animal model selection

Subcutaneous (s.c.) administration continues to be the main route for the d elivery of protein drugs due to their poor bioavailability by most non-pare nteral routes. While small drug molecules are rapidly and extensively absor bed after s.c. injection, the systemic bioavailability of protein drugs is often incomplete and variable. Given the widespread use of the s.c. route f or protein drugs, surprisingly little is known about the factors that gover n 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 th e systemic circulation. The few studies that have directly addressed the ro le of lymphatic transport in protein bioavailability are complicated by the use of methods and models that vary widely. In this review we will evaluat e the available literature describing the lymphatic transport of proteins a fter s.c. injection and more specifically, address the impact of experiment al variation (e.g. site of cannulation, animal model, anesthesia) on the in terpretation of the data obtained. We will also describe in some detail the sheep model currently in use in our laboratory, which allows both estimati on of the extent of uptake of protein drugs into the lymphatics draining th e injection site, and quantification of the contribution of lymphatic trans port to the absolute bioavailability. (C) 2001 Elsevier Science B.V. All ri ghts reserved.