Received for publication March 13, 2007.
Revised September 13, 2007.
Accepted for publication September 14, 2007.

Lymphatic absorption of subcutaneously administered proteins: Influence of different injection sites on the absorption of Darbepoetin alfa using a sheep model

Abstract

The relative contribution of the lymph and blood in the absorption of Darbepoetin alfa (DA) from different subcutaneous (SC) injection sites was determined using a central lymph-cannulated sheep model. DA was administered to parallel groups either as a bolus intravenous (IV) injection (0.5 µg/kg) into the jugular vein, or as a bolus SC injection (2 µg/kg) into the interdigital space, the abdomen or the shoulder. In the lymph-cannulated groups, the thoracic lymph duct was cannulated for continuous collection of central lymph, and blood samples were periodically collected via the jugular vein in all groups. The concentration of DA in serum and lymph was determined by ELISA. The total fraction of the dose reaching the systemic circulation and the fractions absorbed via the lymph and the blood were determined. A pharmacokinetic model was constructed to simultaneously fit the data from all treatment groups. Absorption was essentially complete for all three injection sites in non-lymph-cannulated SC groups, but the rates of absorption differed significantly. Based on the modelling results for the lymph-cannulated groups, the lymphatics represented the predominant absorption route for both the interdigital (90 ± 1%) and the abdomen (67 ± 9%) injection sites. FITC dextran visualization studies revealed that the lymph draining the shoulder injection site entered the thoracic lymph duct distal to the point of cannulation, effectively precluding collection of thoracic lymph from this site. For that reason, the contribution of the lymphatics following injection in the shoulder could not be determined using these cannulation procedures.

Key words: drug absorption, drug delivery, drug disposition, pharmacokinetic modeling, recombinant proteins