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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Lymphatic Absorption Is the Primary Contributor to the Systemic Availability of Epoetin Alfa following Subcutaneous Administration to Sheep

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia (D.N.M., C.J.H.P., S.A.C.); Department of Veterinary Sciences, University of Melbourne, Werribee, Victoria, Australia (G.A.E.); and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California (S.W.M., A.C.H.)

The contribution of the lymphatics to the absorption and systemic availability of recombinant human epoetin alfa (rHuEPO) following s.c. injection was examined using a cannulated sheep model. Parallel studies were conducted in sheep where a single bolus dose was administered either by i.v. (10, 100, or 1000 IU/kg) or s.c. (400 IU/kg) injection. The first s.c. group served as a control for the calculation of absolute bioavailability. In the second group, the efferent popliteal lymphatic duct was cannulated and peripheral lymph draining the injection site was continuously collected. In the third group, the thoracic duct was cannulated to allow collection of central lymph just prior to entry into the systemic circulation. Blood was periodically sampled from all animals, and concentrations in serum and lymph were determined by enzyme-linked immunosorbent assay. The cumulative amount of rHuEPO recovered in peripheral and central lymph was 83.9 ± 6.6% and 75.3 ± 3.9% of the administered dose, respectively, indicating almost complete absorption from the s.c. injection site and minimal clearance during transit through the lymphatic system. After i.v. administration, the systemic clearance of rHuEPO decreased with increasing dose, reflecting capacity-limited elimination kinetics. A pharmacokinetic model was developed to simultaneously fit experimental data for all treatment groups and estimate bioavailability. The direct measurement of >75% of the dose in peripheral and central lymph independently verifies the calculated bioavailability of 87% and demonstrates the major role of the lymphatic route in the overall s.c. bioavailability of rHuEPO after s.c. administration with this animal model.

Address correspondence to: Dr. Susan Charman, Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. E-mail: susan.charman{at}vcp.monash.edu.au

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