title: In vitro and in vivo stability and pharmacokinetic profile of unacylated ghrelin (UAG) analogues.
abstract: Ghrelin, an endocrine hormone predominantly produced by the stomach, exists in acylated and unacylated forms in the circulation. Unacylated ghrelin (UAG), the more abundant form in blood, possesses similar, independent or opposite physiological actions as acylated ghrelin (AG). AZP502, a linear 8-amino acid peptide from the central region of UAG (UAG(6-13)), and its full (AZP531) and partially (AZP533) cyclised derivatives, exhibit the same pharmacological profile as UAG both in vitro and in vivo, independently of AG receptor binding. We investigated the stability of these three fragments in vitro in human blood samples and in vivo after subcutaneous and intravenous injection in rats and dogs using liquid chromatography-mass spectrometry. In both species, AZP502 is rapidly degraded generating two major metabolites. Partial cyclisation of AZP502 and acylation at its N-terminus (AZP533 peptide) improves its stability in human plasma in vitro. Full cyclisation of AZP502 (AZP531 peptide) also completely protects the peptide from peptidase degradation in vitro in human blood samples. Moreover this cyclisation strongly improves the stability and the bioavailability of this peptide in vivo in both dogs and rats (mean bioavailability of 10-15% and 85-95% for AZP502 and AZP531 respectively). Taken together these results support the rationale for developing AZP531 as a long-acting UAG analogue for subcutaneous injection for the treatment of type 2 diabetes mellitus and other metabolic disorders.
authors: Alizé Pharma SAS, 15 Chemin du Saquin, Espace Européen, Building G, 69130 Ecully, France. mjulien@alz-pharma.com
authors: Michel
authors: M
authors: Julien
authors: Richard G
authors: RG
authors: Kay
authors: Patric J D
authors: PJ
authors: Delhanty
authors: Soraya
authors: S
authors: Allas
authors: Riccarda
authors: R
authors: Granata
authors: Chris
authors: C
authors: Barton
authors: Scott
authors: S
authors: Constable
authors: Ezio
authors: E
authors: Ghigo
authors: Aart J
authors: AJ
authors: van der Lely
authors: Thierry
authors: T
authors: Abribat
mesh_terms: D000215:Acylation; D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004285:Dogs; D004355:Drug Stability; D005260:Female; D054439:Ghrelin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D036361:Peptide Hormones / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000378:metabolism
chemical_list: D054439:Ghrelin; D036361:Peptide Hormones; D054440:Receptors, Ghrelin