Pharmacokinetics of intranasal, intramuscular and intravenous glucagon in healthy subjects and diabetic patients

Abstract

The pharmacokinetics of intranasal, an intravenous infusion, and intramuscular glucagon has been studied in 5 healthy subjects and 11 patients with insulin-dependent diabetes mellitus. After infusion the elimination half-life was significantly longer in diabetics (11.9 vs 6.6 min) and the apparent volume of distribution was twice as high in diabetics (0.19 vs 0.37 l.kg-1). The metabolic clearance rates were the same in the two groups (18.9 and 21.3 ml.min-1.kg-1 in controls and in diabetics) and were about twice those previously reported. After 1 mg intranasally the Cmax of immunoreactive glucagon (IRG) was similar in diabetic and in healthy subjects. Administration of a higher dose (2 mg) to diabetic patients produced a higher plasma level, although not proportionately so. The AUC after 1 mg was also similar in controls and in diabetics. The elimination half-life in both groups was similar to the value found after i.v. infusion; it was significantly shorter in controls (5.5 min) than in diabetics (13.8 min). In both groups, mean Cmax was significantly lower than after IM glucagon, the relative bioavailability of 1 mg intranasally vs IM injection being less than 30%. After IM administration, the Cmax and AUC of IRG in controls and in diabetic patients, were identical. The apparent elimination half-life was also similar in the two groups, and was three- to four-times longer (28.6 and 31.4 min) than after infusion or intranasal administration, possibly because estimation of the t1/2 was affected by slow release of the hormone from the site of injection.

Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease

“…Much of glucagon removal is through receptor-mediated endocytosis, but there is evidence for endovascular proteolysis by dipeptididyl peptidase IV (318) and enzymatic degradation at the level of the plasma membrane (31,117). The half-life of glucagon in circulating plasma is relatively short: 2, 5, and 7 min in rats, dogs, and humans, respectively (14,316).…”

Factors Influencing the Effectiveness of Glucagon for Preventing Hypoglycemia

“…4 Glucagon acts to rapidly raise blood glucose in both persons with and without diabetes by catabolizing liver glycogen. 9 In general terms, in an insulin and glucagon closed-loop system, insulin is delivered nearly continuously to treat and prevent hyperglycemia, and glucagon is delivered intermittently to treat and prevent hypoglycemia. When used in this manner, glucagon decreased hypoglycemia by two-thirds, from an average of 40 min/day in the hypoglycemic range to 15 min/day.…”

A Review of Potential Cardiovascular Uses of Intravenous Glucagon Administration

“…9 Since the elimination half-life is short (around 6 minutes), the effect of a single bolus dose cannot be expected to last more than 30 minutes. 8,9,31 This may be particularly important in an overdose with an agent that has a long innate halflife or is pharmaceutically prepared in a sustained release form. 13 The use of a continuous infusion can maintain the glucagon concentration but may not prolong the inotropic and chronotropic effect over the long term.…”

“…7 The half-life of intravenous glucagon is 6.6 minutes in normal patients but approximately 12 minutes in diabetics. 8 Glucagon is a counter-regulatory hormone that is classically used to treat hypoglycemia. However, it can elicit the generation of cAMP within the myocardium to cause positive inotropic and chronotropic effects without the need for beta-1 adrenoceptor stimulation.…”

“…9 The clearance of glucagon is approximately 19 mL/min Kg, and the volume of distribution is low at approximately 0.2 L/kg. 8 Glucagon is eliminated in tissues, plasma, liver, and the kidney, although the main route of elimination has not been determined. 10…”