Pharmacokinetics of Intraperitoneally Delivered Glucagon in Pigs: A Hypothesis of First Pass Metabolism

Abstract

Background and Objective Artificial pancreases administering low-dose glucagon in addition to insulin have the scope to improve glucose control in patients with diabetes mellitus type 1. If such a device were to deliver both hormones intraperitoneally, it would mimic normal physiology, which may be beneficial. However, the pharmacokinetic properties of glucagon after intraperitoneal administration are not well known. Hence, the current study aims to evaluate the relationship between the amount of intraperitoneally delivered glucagon and pharmacokinetic variables in a pig model. Methods Pharmacokinetic data was retrieved from experiments on 19 anaesthetised pigs and analysed post hoc. The animals received a single intraperitoneal bolus of glucagon ranging from 0.30 to 4.46 µg/kg. Plasma glucagon was measured every 2–10 min for 50 min. Results Peak plasma concentration and area under the time–plasma concentration curve of glucagon correlated positively with the administered dose, and larger boluses provided a relatively greater increase. The mean (standard deviation) time to maximum glucagon concentration in plasma was 11 (5) min, and the mean elimination half-life of glucagon in plasma was 19 (7) min. Conclusions Maximum plasma concentration and area under the time–plasma concentration curve of glucagon increase nonlinearly in relation to the intraperitoneally administered glucagon dose. We hypothesise that the results are compatible with a satiable first-pass metabolism in the liver. Time to maximum glucagon concentration in plasma and the elimination half-life of glucagon in plasma seem independent of the drug dose.