Linking (Pyr)1apelin-13 pharmacokinetics to efficacy: Stabilization and measurement of a high clearance peptide in rodents.
Anal Biochem
; 568: 41-50, 2019 03 01.
Article
em En
| MEDLINE
| ID: mdl-30605634
ABSTRACT
Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Peptídeos e Proteínas de Sinalização Intercelular
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article