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Lymphatic Absorption of Subcutaneously Administered Proteins: Influence of Different Injection Sites on the Absorption of Darbepoetin Alfa Using a Sheep Model

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia (J.K., K.K.M., D.N.M., C.J.H.P., S.A.C.); and Department of Veterinary Sciences, University of Melbourne, Werribee, Victoria, Australia (G.A.E.)

The relative contribution of the lymph and blood in the absorption of darbepoetin alfa (DA) from different s.c. injection sites was determined using a central lymph-cannulated sheep model. DA was administered to parallel groups either as a bolus i.v. injection (0.5 µg/kg) into the jugular vein or as a bolus s.c. 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 the groups. The concentration of DA in serum and lymph was determined by enzyme-linked immunosorbent assay. 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 the treatment groups. Absorption was essentially complete for all three injection sites in non–lymph-cannulated s.c. groups, but the rates of absorption differed significantly. Based on the modeling 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. Fluorescein isothiocyanate 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.