Pharmacokinetics and metabolism studies on the glucagon-like peptide-1 (GLP-1)-derived metabolite GLP-1(9-36)amide in male Beagle dogs. (September 2014)

• Record Type: Journal Article
• Authors: Eng, Heather; Sharma, Raman; McDonald, Thomas S.; Landis, Margaret S.; Stevens, Benjamin D.; Kalgutkar, Amit S.
• Is Part Of: Xenobiotica. Volume 44:Number 9(2014:Sep.)
• Page Start: 842
• Page End: 848
• Publication Date: 2014-09
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.897011
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. Glucagon-like peptide-1 (GLP-1)(7-36)amide is a 30-amino acid peptide hormone that is secreted from intestinal enteroendocrine L-cells in response to nutrients. GLP-1(7-36)amide possesses potent insulinotropic actions in the augmentation of glucose-dependent insulin secretion. GLP-1(7-36)amide is rapidly metabolized by dipeptidyl peptidase-IV to yield GLP-1(9-36)amide as the principal metabolite. Contrary to the earlier notion that peptide cleavage products of native GLP-1(7-36)amide [including GLP-1(9-36)amide] are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with GLP-1(9-36)amide in mice, dogs and humans.</p> <p>2. In the present work, <italic>in vitro</italic> metabolism and pharmacokinetic properties of GLP-1(9-36)amide have been characterized in dogs, since this preclinical species has been used as an animal model to demonstrate the <italic>in vivo</italic> vasodilatory and cardioprotective effects of GLP-1(9-36)amide. A liquid chromatography tandem mass spectrometry assay was developed for the quantitation of the intact peptide in hepatocyte incubations as opposed to a previously reported enzyme-linked immunosorbent assay. Although GLP-1(9-36)amide was resistant to proteolytic cleavage in dog plasma and bovine serum albumin (<italic>t</italic><sub>1/2</sub> > 240 min), the peptide was rapidly metabolized in dog hepatocytes with a <italic>t</italic><sub>1/2</sub> of 110 min. Metabolite identification studies in dog hepatocytes revealed a variety of <italic>N</italic>-terminus cleavage products, most of which, have also been observed in human and mouse hepatocytes. Proteolysis at the <italic>C</italic>-terminus was not observed in GLP-1(9-36)amide.</p> <p>3. Following the administration of a single intravenous bolus dose (20 µg/kg) to male Beagle dogs, GLP-1(9-36)amide exhibited a mean plasma clearance of 15 ml/min/kg and a low steady state distribution volume of 0.05 l/kg, which translated into a short elimination half life of 0.05 h. Following subcutaneous administration of GLP-1(9-36)amide at 50 µg/kg, systemic exposure of GLP-1(9-36)amide as ascertained from maximal plasma concentrations and area under the plasma concentration–time curve from zero to infinity was 44 ng/ml and 32 ng h/ml, respectively. The subcutaneous bioavailability of GLP-1(9-36)amide in dogs was 57%.</p> <p>4. Our findings raise the possibility that the cardioprotective effects of GLP-1(9-36)amide in the conscious dog model of pacing-induced heart failure might be due, at least in part, to the actions of additional downstream metabolites, which are obtained from proteolytic cleavage of the peptide backbone in the parent compound in the liver.</p> </abstract>