Pharmacokinetic Model to Describe the Lymphatic Absorption of r-metHu-Leptin After Subcutaneous Injection to Sheep

Purpose. The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep.Methods. r-metHu-Leptin was administered either by bolus intravenous injection (0.1 mg/kg) into the jugular vein or by SC injection (0.15 mg/kg) into the interdigital space of the hind leg. The SC groups included a non-cannulated control group and a lymph-cannulated group, in which peripheral lymph was continuously collected from a cannula in the efferent popliteal lymph duct. Serum and lymph concentrations were determined by enzyme-linked immunosorbent assay and profiles were modeled using compartmental pharmacokinetic methods. The fraction of the dose reaching the systemic circulation (F_sys) and the proportions of the absorbed dose taken up via the blood (F_blood) and lymph (F_lymph) were determined.Results. Serum and lymph concentration vs. time profiles were well described by a two compartment model with parallel first order absorption into blood and lymph. F_sys for the SC control group was 60.4 ± 8.4%. In the lymph-cannulated group, 21.7 ± 6.4% of the dose was recovered in serum and 34.4 ± 9.7% was recovered in peripheral lymph giving a total fraction absorbed (F_abs) of 56.0 ± 10.3%. F_sys for the SC control group was not significantly different to F_abs in the lymph-cannulated group.Conclusion. This study has shown that the lymph represents the predominant pathway for absorption of r-metHu-Leptin after SC administration.