Pharmacokinetic model to describe the lymphatic absorption of r-metHu-leptin after subcutaneous injection to sheep

Abstract

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 (Fsys) and the proportions of the absorbed dose taken up via the blood (Fblood) and lymph (Flymph) 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. Fsys 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 (Fabs) of 56.0 +/- 10.3%. Fsys for the SC control group was not significantly different to Fabs 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.