Ksenia Shestakova1,2, Alex Brito1, Natalia V Mesonzhnik1, Natalia E Moskaleva1, Ksenia O Kurynina1, Natalia M Grestskaya3, Igor V Serkov4, Igor I Lyubimov5, Vladimir V Bezuglov3, Svetlana A Appolonova6. 1. Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya St., Moscow, Russia, 119991. 2. PhD Program in Nanoscience and Advanced Technology, Department of Diagnostics and Public Health, University of Verona, Policlinico G.B. Rossi - P.le L.A. Scuro 10, 37134, Verona, Italy. 3. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Ulitsa Miklukho-Maklaya, 16/10, Moscow, Russia, 117997. 4. Institute of Physiologically Active Compounds RAS, Severniy pr., 1, Chernogolovka, Russia, 142432. 5. LLC "Gurus BioPharm", Territory of Skolkovo Innovation Center, Bolshoy Boulevard, 42 Building 1, Moscow, Russia, 143026. 6. Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University, 2-4 Bolshaya Pirogovskaya St., Moscow, Russia, 119991. svetlana.appolonova@labworks.ru.
Abstract
INTRODUCTION: Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis). OBJECTIVES: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo. METHODS: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n = 6 in each group). Untargeted (5880 initial features; 1869 negative-4011 positive ion peaks; UPLC-IT-TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC-QQQ-MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 min after administration. RESULTS: PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e., cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate D-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadipic acid and uric acid increased (p < 0.05 AUCROC curve > 0.75) after treatment. Purines (i.e., xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids L-tryptophan and L-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others. CONCLUSION: Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites (i.e., guanine, adenine, cortisol, cortisone and aspartate) involved in purine metabolism, urea and ammonia biological cycles, steroidogenesis, among other pathways. Suggested mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.
INTRODUCTION:Nitroproston® is a novel multi-target drug bearing natural prostaglandin E2 (PGE2) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis). OBJECTIVES: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo. METHODS: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n = 6 in each group). Untargeted (5880 initial features; 1869 negative-4011 positive ion peaks; UPLC-IT-TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC-QQQ-MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 min after administration. RESULTS:PGE2, 13,14-dihydro-15-keto-PGE2, PGB2, 1,3-GDN and 15-keto-PGE2 increased in the treatment group. Steroids (i.e., cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate D-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadipic acid and uric acid increased (p < 0.05 AUCROC curve > 0.75) after treatment. Purines (i.e., xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids L-tryptophan and L-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others. CONCLUSION:Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites (i.e., guanine, adenine, cortisol, cortisone and aspartate) involved in purine metabolism, urea and ammonia biological cycles, steroidogenesis, among other pathways. Suggested mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.
Authors: Natalia V Mesonzhnik; Natalia E Moskaleva; Ksenia M Shestakova; Ksenya O Kurynina; Pavel A Baranov; Natalia M Gretskaya; Igor V Serkov; Igor I Lyubimov; Vladimir V Bezuglov; Svetlana A Appolonova Journal: Drug Metab Lett Date: 2018
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Authors: Ksenia M Shestakova; Natalia E Moskaleva; Natalia V Mesonzhnik; Alexey V Kukharenko; Igor V Serkov; Igor I Lyubimov; Elena V Fomina-Ageeva; Vladimir V Bezuglov; Mikhail G Akimov; Svetlana A Appolonova Journal: Molecules Date: 2020-12-13 Impact factor: 4.411