Lymphatic absorption is a significant contributor to the subcutaneous bioavailability of insulin in a sheep model

Purpose. This study was conducted to explore the role of the peripheral lym phatics in insulin absorption following subcutaneous (SC) administration us ing a sheep model that allows continuous collection of peripheral lymph and simultaneous assessment of systemic bioavailability. Methods: In a parallel group design, soluble human insulin (0.5 IU/ kg) was administered by bolus SC injection into the interdigital space of the hind leg of non-cannulated control sheep, and sheep in which the efferent popli teal lymph duct was cannulated. A separate group received a bolus IV inject ion (0.15 IU/kg). Blood was sampled from all animals, and lymph was collect ed continuously over 12 h postdosing. Samples were assayed for insulin by E LISA. Results. The SC bioavailability of insulin in control sheep was 31.5 +/- 3. 2%, which was significantly higher than when the peripheral lymph was conti nuously collected (18.4 +/- 1.7%). In the lymph-cannulated animals, 17.3 +/ - 1.0% of the dose was collected in peripheral lymph. Conclusions. Based on the direct measurement of insulin in regional lymph and on the decrease in the systemic bioavailability when rea gional lymph was continuously collec ted, the results demonstrate that lymphatic absorption contributed signific antly to the overall insulin bioavailability following SC administration to sheep.