Abstract
The mechanism underlying subcutaneous (SC) absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the SC injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. Following SC administration, the serum exposure was reduced by ~70% in LDC animals when compared to the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta following SC administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat SC tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs were shown to be 2- to 4- fold lower in "fat rats", indicating that physiological features pertinent to lymphatic transport can have a profound impact on SC absorption. Limited studies in dogs also suggested similar SC absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is likely conserved among commonly used preclinical species, e.g. rats and dogs, and that mechanistic understanding of SC absorption mechanism and associated determinants should be helpful in biologics drug discovery and development.
- Received November 10, 2011.
- Accepted February 10, 2012.
- The American Society for Pharmacology and Experimental Therapeutics