DEUTERIUM AS A TOOL FOR CHANGING THE PROPERTIES OF PHARMACEUTICAL SUBSTANCES (REVIEW)

ANTON V. SYROESHKIN; TATYANA V. PLETENEVA; ELENA V. USPENSKAYA; OLGA V. LEVITSKAYA; IRINA V. TARABRINA; SVITLANA N. NOVIKOVA; IGOR A. ZLATSKIY

doi:10.22159/ijap.2021v13i4.41818

Authors

ANTON V. SYROESHKIN Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
TATYANA V. PLETENEVA Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
ELENA V. USPENSKAYA Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
OLGA V. LEVITSKAYA Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
IRINA V. TARABRINA Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow, 117198, Russian Federation
SVITLANA N. NOVIKOVA State Institute of Genetic and Regenerative Medicine NAMS of Ukraine, 67 Vyshgorodska Str., Kyiv 04114, Ukraine
IGOR A. ZLATSKIY State Institute of Genetic and Regenerative Medicine NAMS of Ukraine, 67 Vyshgorodska Str., Kyiv 04114, Ukraine

DOI:

https://doi.org/10.22159/ijap.2021v13i4.41818

Keywords:

Deuterated pharmaceutical substances, Deuterium depleted water, Kinetic isotope effect of deuterium

Abstract

The review is devoted to the influence of the hydrogen isotope–deuterium on biological models of organisms and the biological activity of pharmaceutical substances.

The positions of the influence of deuterium on the properties of active pharmaceutical ingredients and excipients are examined from different perspectives. The first position reflects an increase in the kinetic isotope effect (KIE) in processes involving known pharmaceutical substances in aqueous solutions with a deuterium/protium ratio (D/H) below natural. For the first time, the dose-response diagram shows the identity of deuterium with essential trace elements, when a deficiency and excess of an element reduces the organism's vitality. Improved kinetic characteristics are demonstrated for the molecular and organism levels of different hierarchical gradations. In particular, they consist in the possibility of increasing the dissolution rate of substances by influencing the carbohydrate mutarotation processes and the optical activity of chiral substances, increased accumulation of essential elements in medicinal plants and other processes associated with a possible change in metabolic pathways in the cell and the organism as a whole.

The second considered position of the influence of deuterium is associated with the use of deuterated substances–new compounds or obtained by substitution of protium in known protium analogues. The KIE is presented, which is expressed in a decrease in the biotransformation rate as a result of deuteration, it allows predicting a rapid development of the new direction in the development of drugs. Having an identical therapeutic effect, deuterated analogs provide improved pharmacokinetic characteristics, such as reduced toxicity, blocked epimerization of optically active substances, and a change in the mechanisms of biotransformation. The obtained results make it possible to predict the mechanisms of the effect of deuterium on the biochemical transformations of pharmaceutical substances in the organism.

Downloads

Download data is not yet available.

References

Atzrodt J, Derdau V, William J, Reid M. Deuterium-and tritium-labeled compounds: applications in the life sciences. Angew Chem Int Ed 2018;57:1758-84.

Anton Syroeshkin, Olga Levitskaya, Elena Uspenskaya, Tatiana Pleteneva. Deuterium depleted water as an adjuvant in the treatment of cancer. Sys Rev Pharm 2019;10:112-7.

Zoroddu MA, Aaseth J, Crisponi G, Medici S, Peana M, Nurchi VM. The essential metals for humans: a brief overview. J Inorg Biochem 2019;195:120-9.

Basov A, Fedulova L, Baryshev M, Dzhimak S. Deuterium-depleted water influence on the isotope 2H/1H regulation in body and individual adaptation. Nutr 2019;11:1903.

Tracey Pirali, Marta Serafini, Sarah Cargnin, Armando A. Genazzani applications of deuterium in medicinal chemistry. J Med Chem 2019;62:5276-97.

Roger D Tung. Deuterium medicinal chemistry comes of age. Future Med Chem 2016;8:491-4.

Syroeshkin AV, Pleteneva TV, Uspenskaya EV, Zlatskiy IA, Antipova NA, Grebennikova TV, et al. D/H control of chemical kinetics in water solutions under low deuterium concentrations. Chem Eng J 2019;377:119827.

Goncharuk VV, Syroeshkin AV, Zlatskiy IA, Uspenskaya EV, Orekhova AV, Levitskaya OV, et al. Quasi-chemical description of the kinetics of cell death Spirostomum ambiguum biosensor for the biological activity of aqueous solutions. J Water Chem Techn 2017;39:97-102.

Levitskaya OV, Syroeshkin AV, Pleteneva TV. Arrhenius kinetics as a bioactivity assessment criterion for drug substances and excipients. Pharm Chem J 2016;49:779-81.

Titorovich OV, Lyulina EB, Pleteneva TV, Maksimova TV, Syroeshkin AV, Uspenskaya EV, et al. Reaction of an antioxidant (Sodium Sulfite) with 3-hydroxy-6-methyl-2-ethylpyridinium salts. Pharm Chem J 2015;48:842-4.

Tsisanova ES, Uspenskaya EV, Pleteneva TV, Syroeshkin AV. Study of biological activity and D/H ratio of water with the aid of cellular biosensor spirostomum ambiguum. Trace Elements Med 2010;11:8.

Syroeshkin AV, Pleteneva TV, Uspenskaya EV, Levitskaya OV, Tribot-laspiere MA, Zlatsky IA, et al. Polarimetric research of pharmaceutical substances in aqueous solutions with different water isotopologues ratio. Int J Appl Pharm 2018;10:20182.

Syroeshkin AV, Pleteneva TV, Uspenskaya EV, Levitskaya OV. Optical methods in studies of the chiral properties of drugs I. Valine in water with various deuterium contents. Vedomosti Sci Center Expertise Med Applications 2016;1:25-9.

Goncharuk VV, Lapshin VB, Burdeinaya TN, Pleteneva TV, Chernopyatko AS, Atamanenko ID, et al. Physicochemical properties and biological activity of the water depleted of heavy isotopes. J Water Chem Techn 2011;33:15-25.

Somlyai G, Javaheri B, Davari H, Gyongyi Z, Somlyai I, Tamaddon KA, et al. Pre-clinical and clinical data confirm the anticancer effect of deuterium depletion. Biomacromol J 2016;2:1-7.

Krempels K, Somlyai I, Gyongyi Z, Ember I, Balog K, Abonyi O, et al. Retrospective study of survival in breast cancer patients undergoing deuterium depletion in addition to conventional therapies. J Cancer Res Ther 2013;1:194-200.

Goncharuk VV, Syroeshkin AV, Pleteneva TV, Uspenskaya EV, Levitskaya OV, Tverdislov VA. On the possibility of chiral structure density submillimeter inhomogeneities existing in water. J Water Chem Techn 2017;39:319-24.

Elena V Uspenskaya, Tatyana V Pleteneva, Anton V Syroeshkin, Ilaha V Kazimova, Tatyana E Elizarova, Artem I Odnovorov. Role of stable hydrogen isotope variations in water for drug dissolution managing. Curr Issues Pharm Med Sci 2020;33:94-101.

Zrelov OYu, Syroeshkin AV, Uspenskaya EV, Titorovich (Levitskaya) OV. Effect of water isotopic composition on galactose mutarotation kinetics. Pharm Chem J 2015;49:413-6.

Anton Syroeshkin, Maria Makarova, Tatiana Maksimova, Tatiana Pleteneva, Igor Zlatskiy. Development of zinc-enriched medicinal and food plants. SRP 2020;11:726-31.

Halenova T, Zlatskiy I, Syroeshkin A, Maximova T, Pleteneva T. Deuterium-depleted water as adjuvant therapeutic agent for treatment of diet-induced obesity in rats. Molecules 2020;25:23.

Basov A, Fedulova L, Vasilevskaya E, Dzhimak S. Possible mechanisms of biological effects observed in living systems during 2H/1H isotope fractionation and deuterium interactions with other biogenic isotopes. Molecules 2019;24:4101.

Cisanova ES, Syroeshkin AV, Uspenskaya EV, Ul’yantsev AS, Pleteneva TV, Klimova EV, et al. The study of biological activity and the ratio of deuterium/protium (D/H) in water using a cellular biosensor S. ambiguum. Studied Russia 2010;46:558-93.

Lewis GN. Biology of heavy water. Nature 1934;133:620.

Lobyshev VN, Kalinichenko LP. Isotopic effects in biological systems. Moscow: Nauka; 1978.

Boros LG, D'Agostino DP, Katz HE. Submolecular regulation of cell transformation by deuterium depleting water exchange reactions in the tricarboxylic acid substrate cycle. Med Hypotheses 2016;87:69-74.

Robins RJ, Remaud GS, Billault I. Natural mechanisms by which deuterium depletion occurs in specific positions in metabolites. Eur Chem Bull 2012;1:39-40.

Cleland WW. The use of isotope effects to determine enzyme mechanisms. J Biol Chem 2003;278:51975-84.

Strekalova T, Evansa M, Chernopiatko A, Coucha Y, Costa Nunes J. Deuterium content of water increases depression susceptibility: the potential role of a serotonin-related mechanism. Behav Brain Res 2015;277:237-44.

Cărpinişan L, Petcu MD, Petrovici S, Chis C, Ghise A, Zehan R. The Influence of deuterium depleted water on the hematocrit and the leukocyte formula in rats intoxicated with chromium. Sci Papers: Animal Sci Biotech 2010;43:464-8.

Olariu L, Petcu M, Cuna S, Scurtu M, Tulcan C, Brudiu I. The role of deuterium depleted water (ddw) administration in blood deuterium concentration in Cr (VI) intoxicated rats. Lucrari Stiinłifice Med Veterinara 2010;43:193-6.

Hang M, Huynh V, Meyer TJ. Colossal kinetic isotope effects in proton-coupled electron transfer. PNAS 2004;101:13138-41.

Syroeshkin AV, Antipova NV, Zlatska AV, Zlatskiy IA, Skylska MD, Grebennikova TV, et al. The effect of the deuterium depleted water on the biological activity of the eukaryotic cells. J Trace Elem Med Biol 2018;50:629-33.

Zlatskiy IA, Zlatska AV, Antipova NV, Syroeshkin AV. Effect of deuterium on the morpho-functional characteristics of normal and cancer cells in vitro. Trace Elem Electrolytes 2018;35:211-4.

Zlatskiy IA, Zlatska AV, Antipova NV, Dolenko SA, Gordiienko IM, Gubar OS, et al. Comparative analysis of the different dyes' potential to assess human normal and cancer cell viability in vitro under different D/H ratios in a culture medium. Sci World J 2020. https://doi.org/10.1155/2020/2373021

Zlatska A, Vasyliev RG, Gordiienko IM, Rodnichenko AE, Morozova MA, Vulf MA, et al. Effect of the deuterium on efficiency and type of adipogenic differentiation of human adipose-derived stem cells in vitro. Sci Rep 2020;10:5217.

Zlatskiy I, Pleteneva T, Skripnikov A, Grebennikova T, Maksimova T, Antipova N, et al. Dependence of biocatalysis on D/H ratio: possible fundamental differences for high-level biological taxons. Molecules 2020;25:4173.

Somlyai G, Jancso G, Jakli G, Vass K, Barna B, Lakics V, et al. Naturally occurring deuterium is essential for the normal growth rate of cells. FEBS Lett 1993;317:1-4.

Demmig Adams B, Stewart JJ, Adams WW. Multiple feedbacks between chloroplast and whole plant in the context of plant adaptation and acclimation to the environment. Philos Trans R Soc Lond B Biol Sci 2014;369:20130244.

Buchachenko AL, Kuznetsov DA. Magnesium magnetic isotope effect: A key to the mechanochemistry of phosphorylating enzymes as molecular machines. Mol Biol 2006;40:9-15.

Maret W. The Metals in the biological periodic system of the elements: concepts and conjectures. Int J Mol Sci 2016;17:66.

Dzhimak SS, Basov AA, Baryshev MG. Content of deuterium in biological fluids and organs: influence of deuterium depleted water on D/H gradient and the process of adaptation biochemistry. Bioph Mol Biol 2015;465:370-3.

Yavari K, Kooshesh L. Deuterium depleted water inhibits the proliferation of human MCF7 breast cancer cell lines by inducing cell cycle arrest. Nutr Cancer 2019;71:1019-29.

Gyongyi F, Budan I, Szabo W. Deuterium depleted water effects on survival of lung cancer patients and expression of kras, Bcl2, and Myc genes in mouse lung. Nutr Cancer 2013;65:240-6.

Tracey Pirali, Marta Serafini, Sarah Cargnin, Armando A. Genazzani applications of deuterium in medicinal chemistry. J Med Chem 2019;62:5276-97.

Kovacs A, Guller I, Krempels K, Somlyai I, Janosi I, Gyöngyi Z. Deuterium depletion may delay the progression of prostate cancer. J Cancer Ther 2011;2:548-56.

Thulasiram HV, Phan RM, Rivera SB, Poulter CD. Synthesis of deuterium-labeled derivatives of dimethylallyl diphosphate. J Org Chem 2006;71:1739-41.

Sattler A. Hydrogen/Deuterium (H/D) exchange catalysis in alkanes. ACS Catal 2018;8:2296-312.

Belleau B, Burba J, Pindell M, Reiffenstein J. Effect of deuterium substitution in sympathomimetic amines on adrenergic responses. Science 1961;133:102-4.

Elison C, Rapoport H, Laursen R, Elliott HW. Effect of deuteration of N–CH3 group on potency and enzymatic N-demethylation of morphine. Science 1961;134:1078-9.

Sipes IG, Gandolfi AJ, Pohl LR, Krishna G, Brown BR. Comparison of the biotransformation and hepatotoxicity of halothane and deuterated halothane. J Pharmacol Exp Ther 1980;214:716-20.

Claassen DO, Carroll B, De Boer LM, Wu E, Ayyagari R, Gandhi S, et al. Indirect tolerability comparison of deutetrabenazine and tetrabenazine for huntington disease. J Clin Mov Disord 2017;4:3-13.

Garay RP, Grossberg GT. AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type. Expert Opin Invest Drugs 2017;26:121-32.

Xie JH, Gillooly K, Zhang Y, Yang X, Zupa Fernandez A, Cheng L, et al. 349-BMS-986165 is a highly potent and selective allosteric inhibitor of TYK2, blocks IL-12, IL-23 and type I interferon signaling and provides for robust efficacy in preclinical models of systemic lupus erythematosus and inflammatory bowel disease. Gastroenterology 2018;154:S-1357.

Khan AJ, Misenko SM, Thandoni A, Schiff D, Jhawar SR, Bunting SF, et al. VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells. Oncotarget 2018;9:25833-41.

First-in-human study of the safety. Tolerability, and Pharmacokinetic/Pharmacodynamic profile of VX-984 in combination with chemotherapy. Available from: clinicaltrials. govidentifier:NCT02644278. [Last accessed on 15 Nov 2018]

Hearn BR, Fontaine SD, Pfaff SJ, Schneider EL, Henise J, Ashley GW, et al. Primary deuterium kinetic isotope effects prolong drug release and polymer biodegradation in a drug delivery system. J Controlled Release 2018;278:74-9.

Malmlof T, Rylander D, Alken RG, Schneider F, Svensson TH, Cenci MA, et al. Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias. Exp Neurol 2010;225:408-15.

Calinski DM, Zhang H, Ludeman S, Dolan ME, Hollenberg PF. Hydroxylation and N-dechloroethylation of ifosfamide and deuterated ifosfamide by the human cytochrome p450s and their commonly occurring polymorphisms. Drug Metab Dispos 2015;43:1084-90.

Bhadra PB, Hassanzadeh A, Arsic B, Allison DG, Morris GA, Barber J. Enhancement of the properties of a drug by monodeuteriation: reduction of acid-catalyzed formation of a gut-motilide enol ether from 8-deuterio-erythromycin B. Org Biomol Chem 2016;14:6289-96.

Shao L, Abolin C, Hewitt MC, Koch P, Varney M. Derivatives of tramadol for increased duration of effect. Bioorg Med Chem Lett 2006;16:691-4.

Smith SW. Chiral toxicology: It’s the same thing..only different. Toxicol Sci 2009;110:4-30.

Csuk R. Biocatalysis in the pharma and biotech industries. CRC Press: Boca Raton FL; 2007. p. 699-716.

Hutt AJ, Valentova J. The chiral switch: the development of single enantiomer drugs from racemates. Acta Fac Pharm Univ Comenianae 2003;50:7-23.

Ali I. Homochiral drug design and development by racemization. Comb Chem High Throughput Screening 2007;10:326-35.

Somogyi A, Bochner F, Foster D. Inside the isomers: the tale of chiral switches. Aust Prescr 2004:27:47-9.

Mori T, Ito T, Liu S, Ando H, Sakamoto S, Yamaguchi Y, et al. Structural basis of thalidomide enantiomer binding to cereblon. Sci Rep 2018;8:1294-307.

Yamamoto T, Tokunaga E, Nakamura S, Shibata N, Toru T. Synthesis and configurational stability of (S)-and (R)-deuteriothalidomides. Chem Pharm Bull 2010;58:110-2.

Jacques V, Czarnik AW, Judge TM, Van der Ploeg LH, DeWitt SH. Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc Natl Acad Sci USA 2015;112:E1471-9.

Mullard A. Deuterated drugs draw heavier backing. Nat Rev Drug Discovery 2016;15:219-21.

Graham S Timmins. Deuterated drugs; where are we now? Expert Opin Ther Pat 2014;24:1067-75.

Tripathy S, Mohanty PK. Mesenchymal stem cells: an innovative approach in pharmacokinetics. Asian J Pharm Clin Res 2017;10:25-36.

Viswanathan B, Tks S, Chida AR, Stanly DM. Physiologically-based pharmacokinetic model for plant-based anti-oxidant drugs. Asian J Pharm Clin Res 2016;9:223-9.

Pathare B, Tambe V, Patil V. A review on various analytical methods used in determination of dissociation constant. Int J Pharm Pharm Sci 2014;6:26-34.

Saxena A, Gupta AK, Nainar MS, Bob M, Kasibhatta R. Quantification of urapidil in human plasma using ultra-performance liquid chromatography-electrospray ionization mass spectrometry (uplc-ms/ms) for pharmacokinetic study in healthy indian volunteers. Int J Pharm Pharm Sci 2014;6:565-70.