1. In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug.
- Author
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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, and Amoroso, Rosa
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METABOLITES ,PROLINE ,LIQUID chromatography-mass spectrometry ,PERIPHERAL vascular diseases ,VASCULAR smooth muscle ,METABOLOMICS ,SMOOTH muscle ,ADENOSINES - Abstract
Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E
1 (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. [ABSTRACT FROM AUTHOR]- Published
- 2020
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