scholarly journals Pharmacokinetic Study of SKL-18287, a Novel Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, in Rats, Monkeys and Mini-Pigs

Drug Research ◽  
2019 ◽  
Vol 69 (09) ◽  
pp. 479-486
Author(s):  
Mitsuaki Takeuchi ◽  
Masayuki Okamoto ◽  
Miyuki Tamura ◽  
Takayo Murase ◽  
Nobuhide Watanabe
Keyword(s):  
Half Life ◽  
Animal Species ◽  
Subcutaneous Administration ◽  
The United States ◽  
Pharmacokinetic Parameters ◽  
Target Tissue ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting ◽  
Mini Pigs

Abstract Background Long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for treatment of type 2 diabetes (T2DM) in the United States, the European Union, and Japan. In our previous work, we designed and characterized a novel GLP-1 RA, SKL-18287. This RA consists of only natural L-amino acids, and is believed to exist in an oligomer form in systemic circulation. This unique feature may allow high biological stability and a long-lasting glucose lowering effect in T2DM treatment. In the present study, we investigated the pharmacokinetic properties of SKL-18287 in rats, monkeys, and mini-pigs. Tissue distributions of radioactivity were also studied in rats after subcutaneous administration of [3H]-SKL-18287. Methods Plasma concentrations of SKL-18287 were measured by LC-MS/MS after intravenous and subcutaneous administration of SKL-18287 in rats, monkeys, and mini-pigs. Pharmacokinetic parameters were then calculated and compared among these animal species. Tissue concentrations of radioactivity were determined by liquid scintillation counting following sample combustion, after subcutaneous administration of [3H]-SKL-18287 to rats. Results SKL-18287 showed an extended half-life of over 5 h, with good subcutaneous bioavailability, in all animal species. Prediction of the pharmacokinetic profiles of SKL-18287 in humans using an animal scale-up approach revealed an SKL-18287 half-life of 14.8 h. The radioactivity concentration in the pancreas, a target tissue of GLP-1RA, was relatively higher than in other tissues, until 12 h after [3H]-SKL-18287 administration. Conclusion SKL-18287 might be sufficient to maintain an effective concentration for a once-daily treatment for T2DM, and is a unique GLP-1 RA with a pancreas-selective feature.

scholarly journals Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice

2018 ◽  
Vol 315 (4) ◽  
pp. R595-R608 ◽  
Author(s):  
Jacob D. Brown ◽  
Danielle McAnally ◽  
Jennifer E. Ayala ◽  
Melissa A. Burmeister ◽  
Camilo Morfa ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
Receptor Agonist ◽  
Day Treatment ◽  
Mtor Pathway ◽  
Obese Mice ◽  
Promote Weight Loss ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

scholarly journals The experience with the clinical application of liralgutide (victosa), the first analog of human glucagon-like peptide-1 in the patients with type 2 diabetes mellitus - expanding the range of possibilities

2012 ◽  
Vol 58 (3) ◽  
pp. 51-55
Author(s):  
E N Ostroukhova ◽  
O K Khmel'nitskiĭ ◽  
E I Krasil'nikova ◽  
K S Davidenko
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Body Weight ◽  
Adverse Reactions ◽  
Brand Name ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting

This paper reports the results of the treatment of 71 patients presenting with type 2 diabetes mellitus using liraglutide, a long-acting analog of glucagon-like peptide-1 (GLP-1) marketed under the brand name Victoza. Practically all the patients experienced either improvement or normalization of the parameters of carbohydrate metabolism in conjunction with a reduction of their body weight and arterial pressure. There were no severe hypoglycemic episodes and other adverse reactions to the therapy. It is recommended that Victoza should be more widely used for the treatment of the patients with type 2 diabetes mellitus.

scholarly journals Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Albiglutide, a Long-Acting Glucagon-Like Peptide-1 Mimetic, in Patients with Type 2 Diabetes

2008 ◽  
Vol 93 (12) ◽  
pp. 4810-4817 ◽  
Author(s):  
Jessica E. Matthews ◽  
Murray W. Stewart ◽  
Erika H. De Boever ◽  
Robert L. Dobbins ◽  
Rebecca J. Hodge ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Acting
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