Journal Article

In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug

Serkov, Igor V., Akimov, Mikhail G., Kukharenko, Alexey V., Fomina-Ageeva, Elena V., Bezuglov, Vladimir V., Shestakova, Ksenia M., Lyubimov, Igor I., Appolonova, Svetlana A., Moskaleva, Natalia E., Mesonzhnik, Natalia V.

2020

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: 1,3-dinitroglycerol / Adenosine / Alprostadil - analogs & derivatives / Alprostadil - blood / Alprostadil - pharmacokinetics / Amino acids / Animals / Anti-Inflammatory Agents, Non-Steroidal - chemistry / Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics / Aorta - drug effects / Aorta - metabolism / Chromatography, Liquid / Coronary vessels / Endothelium / Enzymes / Glycerol / Humans / Mass Spectrometry / Metabolic Networks and Pathways / Metabolism / Metabolites / Metabolomics - methods / Myocytes, Smooth Muscle - drug effects / Myocytes, Smooth Muscle - metabolism / Nitric oxide / Nitric Oxide - antagonists & inhibitors / Nitric Oxide - biosynthesis / nitric oxide generation / peripheral arterial disease / Peripheral Arterial Disease - drug therapy / Pharmaceuticals / Pharmacokinetics / Prostanit metabolomic response / Prostanit pharmacokinetics / Rabbits / Smooth muscle / Steroids