Linking (Pyr)1apelin-13 pharmacokinetics to efficacy: Stabilization and measurement of a high clearance peptide in rodents
| Autor: | Claudia Generaux, Heather Finlay, Susan R. Arthur, Mei-Yin Hsu, Roy Haskell, Peter S. Gargalovic, Joelle M. Onorato, Michael Basso, Rongan Zhang, Kimberley A. Lentz, Anne Rose, Carrie Xu, Lei Zhao, Jeffrey S. Bostwick, Gayani Fernando, Ricardo Garcia, Xue-Qing Chen, James Hennan, Michael C. Myers, R. Michael Lawrence, Petia Shipkova, Samuel Hellings |
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| Rok vydání: | 2019 |
| Předmět: |
Gene isoform
chemistry.chemical_classification 0303 health sciences Chemistry 010401 analytical chemistry Biophysics Peptide Cell Biology Pharmacology 01 natural sciences Biochemistry 0104 chemical sciences Apelin Amino acid 03 medical and health sciences Pharmacokinetics Extended release Receptor Molecular Biology Hemodynamic effects 030304 developmental biology |
| Zdroj: | Analytical Biochemistry. 568:41-50 |
| ISSN: | 0003-2697 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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