MSACL 2019 EU Abstract

Pharmacometabolomic Study of Novel Multitarget Drugs Based on Natural Prostaglandins in Terms of Therapeutic Effectiveness

Shestakova K.*(1,2), Mesonzhnik N.(1), Moskaleva N.(1), Bezuglov V.(3), Lubimov I.(4), Serkov I.(3), Appolonova S.(1)
1. Sechenov University. Laboratory of pharmacokinetiks and metabolome analysis, Moscow, Russia; 2. Verona University, PhD program in nanoscience and advanced technologies, department of diognostics and public health, Verona, Italy 3. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia 4. Institute of Physiologically Active Compounds RAS, Moscow, Russia.

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Kseniia Shestakova (Presenter) University of Verona, Sechenov University >> POSTER (PDF)

Presenter Bio: Ksenia Shestakova, born in Moscow on 4th September, 1992. Presently - a PhD student at the mutual PhD program between Sechenov University and Verona University. My scientific interests are focused in different fields of analytical chemistry, primarily- mass-spectrometry (MS) field, as well as its application in metabolomics and proteomics.

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Conflict mitigation NOT REQUIRED.

Introduction. In last few years multi-target drugs have gained high popularity at the drug development market. Its main pharmacological effect is provided by the combined action of hybrid compounds that interact with several targets in the area of one disease. Novel biogenic molecules, prostanit® and nitroproston®, represent an interesting example of multi-target compounds. They are based on natural prostaglandins PGE1 (in prostanit®) and PGE2 (in nitroproston®) linked by a glycerol moiety to two nitric oxide (NO) ‒ donating fragments. Due to biogenic nature of the these pharmaceuticals, as well as rapid integration of their active components into biochemical cycles, metabolism study becomes difficult. To overcome these complexities, metabolomic approaches were used, giving an opportunity to investigate their metabolic pathways, mechanisms of action and therapeutic effectiveness.

Methods. There were conducted in vivo studies randomly assigning the target drugs (treatment groups) or a saline solution without the drug (vehicle control groups) to 12 rabbits (n=6 in each group). Using untargeted (LC-MS-IT-TOF) and targeted (LC-MS/MS) approaches rabbits plasma samples were measured at 10 time-points within 0-60 minutes. Further univariate and multivariate statistical methods were utilized for identification of the metabolites, which concentration levels were induced after drug administration.

Results. The heatmap showed clear discrimination between the vehicle control and treated groups for all found metabolites. Prostanit® and Nitroproston® undergo rapid hydrolysis that results in formation of their two main components: 1,3-dinitro glycerol and Prostglandin E (PGE1 and PGE2, respectively) that are subsequently oxidized to 15-keto-PGE and 13,14-dehydro-15-keto-PGE. We identified that the most significantly changed metabolic pathways, induced after Prostanit® administration were: purine, alanine, glutamate and glutathione metabolism. Moreover, Prostanit® administration activates oxidation processes (e.g. transformation of proline to hydroxyproline). At the same time, Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling. Notably, multiple metabolites identified in our study connected to Nitroproston® have been previously considered as having anti-asthma properties (i.e. cortisol, cortisone, aspartate).

Conclusion. To the best of our knowledge this study is the first that describes the metabolic profiles of drugs based on natural prostaglandins. In this study there were presented suggested mechanisms of action and metabolic pathway interactions of drugs based on natural prostaglandins, as well as useful information for further understanding of their metabolic effects and therapeutic effectiveness.