RT Journal Article
SR Electronic
T1 Lymphatic Absorption, Metabolism, and Excretion of a Therapeutic Peptide in Dogs and Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2206
OP 2214
DO 10.1124/dmd.113.051524
VO 41
IS 12
A1 Yan Zou
A1 Thomas J. Bateman
A1 Christine Adreani
A1 Xiaolan Shen
A1 Paul K. Cunningham
A1 Bo Wang
A1 Tu Trinh
A1 Amy Christine
A1 Xuening Hong
A1 Christian N. Nunes
A1 Chris V. Johnson
A1 Andy S. Zhang
A1 Steve J. Staskiewicz
A1 Matthew Braun
A1 Sanjeev Kumar
A1 Vijay Bhasker G. Reddy
YR 2013
UL http://dmd.aspetjournals.org/content/41/12/2206.abstract
AB 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.