TY - JOUR T1 - Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 952 LP - 962 DO - 10.1124/dmd.111.043604 VL - 40 IS - 5 AU - Weirong Wang AU - Nancy Chen AU - Xiaolan Shen AU - Paul Cunningham AU - Scott Fauty AU - Kimberly Michel AU - Bo Wang AU - Xuening Hong AU - Christine Adreani AU - Christian N. Nunes AU - Chris V. Johnson AU - Kuo-chang Yin AU - Michelle Groff AU - Yan Zou AU - Liming Liu AU - Lora Hamuro AU - Thomayant Prueksaritanont Y1 - 2012/05/01 UR - http://dmd.aspetjournals.org/content/40/5/952.abstract N2 - The mechanism underlying subcutaneous 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 subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ∼70% in LDC animals compared with that in 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 after subcutaneous 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 subcutaneous 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 was shown to be 2- to 4-fold lower in “fat rats,” indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development. ER -