Lymphatic transport and catabolism of therapeutic proteins after subcutaneous administration to rats and dogs.
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.
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp and Dohme Corp., West Point, PA 19486, USA.
Weirong
W
Wang
Nancy
N
Chen
Xiaolan
X
Shen
Paul
P
Cunningham
Scott
S
Fauty
Kimberly
K
Michel
Bo
B
Wang
Xuening
X
Hong
Christine
C
Adreani
Christian N
CN
Nunes
Chris V
CV
Johnson
Kuo-Chang
KC
Yin
Michelle
M
Groff
Yan
Y
Zou
Liming
L
Liu
Lora
L
Hamuro
Thomayant
T
Prueksaritanont
D000042:Absorption; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D004285:Dogs; D055808:Drug Discovery; D004591:Electrophoresis, Polyacrylamide Gel; D004921:Erythropoietin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000378:metabolism; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000502:physiology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D013045:Species Specificity; D013997:Time Factors; D014018:Tissue Distribution
D011994:Recombinant Proteins; C508174:pegylated erythropoietin; D004921:Erythropoietin; D011092:Polyethylene Glycols