Pharmacokinetics and Pharmacodynamic Effects of Oral GLP-1 and PYY3-36: A Proof-of-concept Study in Healthy Subjects

Abstract

This proof-of-concept study was performed in order to establish the pharmacokinetics and pharmacodynamics of increasing oral doses of the satiety peptides glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY3-36). Six healthy male subjects were given oral doses of either a placebo or GLP-1 in a dose-escalating schedule (doses of 0.5, 1.0, 2.0, and 4.0 mg). Next, another group of six healthy male subjects were given oral doses of either a placebo or PYY3-36 in the same pattern of escalating doses (doses of 0.25, 0.5, 1.0, 2.0, and 4.0 mg). In healthy male volunteers, (i) oral administration of either of the peptides induced a rapid and dose-dependent increase in plasma drug concentrations; (ii) oral administration of GLP-1 induced a potent effect on insulin release; and (iii) both peptides suppressed ghrelin secretion. In conclusion, this study showed, for the first time, that satiety peptides such as GLP-1 and PYY3-36 can be orally delivered safely and effectively in humans.

Mesoporous Silicon (PSi) for Sustained Peptide Delivery: Effect of PSi Microparticle Surface Chemistry on Peptide YY3-36 Release

“…It was isolated originally from porcine intestinal and it is able to cross the blood brain barrier through a non-saturable mechanism (20,21). The effects of PYY3-36 on food intake have been investigated in several animal species and also in humans (22,23). In rodents, it has been shown that PYY administration can reduce both food intake and body weight (24).…”

“…A longer lasting clinical trial has also been conducted by Nastech Pharmaceutical Company Inc. (34) using intranasal PYY3-36 with a similar administration frequency as in the previous study. Recently, PYY3-36 has been combined with GLP-1 and the combination was administered orally with a delivery agent SNAC, but elevated plasma concentrations could only be detected for 2 h (23). Since all of these tested delivery systems require repeated administration, a sustained release system would be preferable.…”

Novel Glucagon-like Peptide-1 Analog Delivered Orally Reduces Postprandial Glucose Excursions in Porcine and Canine Models

“…5 Prolonged reductions in both plasma glucose and ghrelin levels were observed, indicating a multifaceted means of controlling food intake. These long-lasting effects stimulated by transient GLP-1 presence are suggestive of stimulation of portal neuronal signaling pathways.…”

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

“…For oral application of GLP-1, the Eligen technology is being investigated (Beglinger et al, 2008). Eligen is a drug delivery agent forming a conformational complex with the peptide that is protected against degradation and helps the peptide to be absorbed.…”