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- Title
In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug.
- Authors
Shestakova, Ksenia M.; Moskaleva, Natalia E.; Mesonzhnik, Natalia V.; Kukharenko, Alexey V.; Serkov, Igor V.; Lyubimov, Igor I.; Fomina-Ageeva, Elena V.; Bezuglov, Vladimir V.; Akimov, Mikhail G.; Appolonova, Svetlana A.; Maccallini, Cristina; Amoroso, Rosa
- Abstract
Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1, and 13,14-dihydro-15-keto-PGE1. Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective.
- Subjects
METABOLITES; PROLINE; LIQUID chromatography-mass spectrometry; PERIPHERAL vascular diseases; VASCULAR smooth muscle; METABOLOMICS; SMOOTH muscle; ADENOSINES
- Publication
Molecules, 2020, Vol 25, Issue 24, p5896
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules25245896