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

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.

Preface to Nitric Oxide Modulators in Health and Disease I

“…Prostanit, i.e., PGE1 dinitroglycerol ester, is a NO-donating PGE1 derivative with vasodilatory and antiplatelet properties. Given its potential therapeutic effect in the management of peripheral arterial disease (PAD), in their study, Shestakova K. M. et al assessed both in vitro and in vivo the pharmacokinetic properties and metabolic activation of Prostanit [ 4 ]. Interestingly, the authors found a double-phase drug activation, which allows not only the direct release of NO but also the stimulation of NOS activity.…”

Combination of Electrochemistry and Mass Spectrometry to Study Nitric Oxide Metabolism and Its Modulation by Compound K in Breast Cancer Cells

“…In general, the results of the Griess reaction are combined with MS results to analyze the NO-related metabolism. However, the Griess reaction cannot allow for real-time detection of NO in live cells as it has limited accuracy and requires lysis of cells . Besides, some side reactions may occur during the Griess reaction, which would disturb the analytical results of the metabolite.…”

“…However, the Griess reaction cannot allow for real-time detection of NO in live cells as it has limited accuracy and requires lysis of cells. 21 Besides, some side reactions may occur during the Griess reaction, which would disturb the analytical results of the metabolite. Electrochemistry, which has the considerable superiorities of low cost, relative simplicity, high temporal− spatial resolution, and high sensitivity, is extensively applied for detecting and quantifying transient release of biochemical molecules (such as NO, dopamine, ROS, etc.)…”