TY - JOUR T1 - Lymphatic Absorption, Metabolism, and Excretion of a Therapeutic Peptide in Dogs and Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2206 LP - 2214 DO - 10.1124/dmd.113.051524 VL - 41 IS - 12 AU - Yan Zou AU - Thomas J. Bateman AU - Christine Adreani AU - Xiaolan Shen AU - Paul K. Cunningham AU - Bo Wang AU - Tu Trinh AU - Amy Christine AU - Xuening Hong AU - Christian N. Nunes AU - Chris V. Johnson AU - Andy S. Zhang AU - Steve J. Staskiewicz AU - Matthew Braun AU - Sanjeev Kumar AU - Vijay Bhasker G. Reddy Y1 - 2013/12/01 UR - http://dmd.aspetjournals.org/content/41/12/2206.abstract N2 - The objective of the current study was to evaluate the mechanism of absorption and metabolism of a PEGylated peptide, MRL-1 (46 kDa), after s.c. dosing in dogs and rats. Thoracic lymph duct-cannulated (LDC) dog and rat models were developed that allowed continuous collection of lymph for up to 8 days. When [3H]MRL-1 was administered s.c. to LDC dogs, ∼73% of the administered radioactivity was recovered in pooled lymph over a period of 120 hours, suggesting that lymphatic uptake is the major pathway of s.c. absorption for this peptide. In agreement with these data, the systemic exposure of radioactivity related to [3H]MRL-1 in LDC dogs was decreased proportionately when compared with that in noncannulated control dogs. After i.v. dosing with [3H]MRL-1 in LDC dogs, 20% of the administered radioactivity was recovered in pooled lymph over 168 hours, suggesting some level of recirculation of radioactivity related to [3H]MRL-1 from the plasma compartment into the lymphatic system. Experiments conducted in the LDC rat model also resulted in similar conclusions. Analysis of injection site s.c. tissue showed significant metabolism of [3H]MRL-1, which provides an explanation for the <100% bioavailability of therapeutic proteins and peptides after s.c. dosing. After s.c. dosing, the major circulating components in plasma were the parent peptide and the PEG-linker [3H]MRL-2. The metabolism profiles in lymph were similar to those in plasma, suggesting that the loss of peptide was minimal during lymphatic transport. After i.v. dosing in rats, [3H]MRL-1 was metabolized and excreted primarily in the urine as metabolites. ER -