Pharmacokinetics and Pharmacodynamics of Phenibut with Their Potential Dependence on Endogenous Hydrogen Sulfide: A Literature Review

Olha Kyrychenko

National Pirogov Memorial Medical University, Vinnytsya, Vinnytsia, Ukraine.

Dmytro Grebeniuk *

National Pirogov Memorial Medical University, Vinnytsya, Vinnytsia, Ukraine.

Oleh Ksenchyn

National Pirogov Memorial Medical University, Vinnytsya, Vinnytsia, Ukraine.

*Author to whom correspondence should be addressed.


Abstract

Aims: The aim of the study was to analyze the current literature data on the pharmacokinetics and pharmacodynamics of phenibut, as well as to evaluate their potential dependence on endogenous hydrogen sulfide.

Materials and Methods: Retrospective analysis of literature data was carried out on the basis of data from Scopus, Web of science, PubMed, ScienceDirect, UpToDate databases, as well as using the Google search service. When searching for information on the investigated problem, various combinations of keywords in Ukrainian and English were used: “phenibut”, “pharmacokinetics”, “pharmacodynamics”, “pharmacology”, “hydrogen sulfide”, “H2S”, “mechanism of action”, “physiology”, “pathophysiology”. During the processing the search results, either the most recent publications (for the last 10 years) or the latest publications on this issue (regardless of the age) were selected. After studying the data of the search results, 38 scientific sources were selected that met the terms of the request.

Results: Despite its promising profile, phenibut is not without certain limitations and problems. Its effectiveness in the treatment of anxiety disorders is considered moderate compared to traditional anxiolytics such as benzodiazepines. In addition, due to the limited number of studies, its safety and potential side effects with long-term use require further study. Overall, phenibut is an interesting and promising drug that deserves further investigation, but limitations of its use may be related to individual characteristics of pharmacokinetics and pharmacodynamics. In our opinion, the cause of such individual characteristics may be certain endogenous factors that vary among different people. One of these endogenous modulators includes hydrogen sulfide, which regulates a wide range of biochemical and physiological processes.

Conclusion: The broad and diverse influence of endogenous hydrogen sulfide on the course of biochemical and physiological processes in the body prompts the study of its potential modulating influence on the pharmacological properties of drugs. A preclinical study of the pharmacokinetics and pharmacodynamics of drugs (in particular, phenibut) taking into account the level of hydrogen sulfide in the body will allow further optimization of therapeutic schemes by adjusting the background level of this transmitter.

Keywords: Phenibut, pharmacokinetics, pharmacodynamics, hydrogen sulfide


How to Cite

Kyrychenko, Olha, Dmytro Grebeniuk, and Oleh Ksenchyn. 2024. “Pharmacokinetics and Pharmacodynamics of Phenibut With Their Potential Dependence on Endogenous Hydrogen Sulfide: A Literature Review”. Asian Journal of Medical Principles and Clinical Practice 7 (1):240-47. https://journalajmpcp.com/index.php/AJMPCP/article/view/229.

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References

Penzak SR, Bulloch M. Phenibut: Review and pharmacologic approaches to treating withdrawal. J Clin Pharmacol. 2024 Feb 10. DOI: 10.1002/jcph.2414. Epub ahead of print. PMID: 38339875.

Jouney EA. Phenibut (β-Phenyl-γ-Aminobutyric Acid): an easily obtainable "dietary supplement" with propensities for physical dependence and addiction. Curr Psychiatry Rep. 2019 Mar 9;21(4):23.

DOI: 10.1007/s11920-019-1009-0. PMID: 30852710.

Weleff J, Kovacevich A, Burson J, Nero N, Anand A. Clinical presentations and treatment of phenibut toxicity and withdrawal: a systematic literature review. J Addict Med. 2023 Jul-Aug 01;17(4):407-417.

DOI: 10.1097/ADM.0000000000001141. Epub 2023 Feb 3. PMID: 37579098.

Mash JE, Leo RJ. Phenibut: A novel nootropic with abuse potential. Prim Care Companion CNS Disord. 2020 Aug 13;22(4):19l02587. DOI: 10.4088/PCC.19l02587. PMID: 32791574.

Vavers E, Zvejniece L, Svalbe B, Volska K, Makarova E, Liepinsh E, Rizhanova K, Liepins V, Dambrova M. The neuroprotective effects of R-phenibut after focal cerebral ischemia. Pharmacol Res. 2016 Nov;113(Pt B):796-801. DOI: 10.1016/j.phrs.2015.11.013. Epub 2015 Nov 24. PMID: 26621244.

Kupats E, Vrublevska J, Zvejniece B, Vavers E, Stelfa G, Zvejniece L, Dambrova M. Safety and tolerability of the anxiolytic and nootropic drug phenibut: A systematic review of clinical trials and case reports. Pharmacopsychiatry. 2020 Sep;53(5):201-208. DOI: 10.1055/a-1151-5017. Epub 2020 Apr 27. PMID: 32340063.

Rägo L, Kiivet RA, Adojaan A, Harro J, Allikmets L. Stress-protection action of beta-phenyl(GABA): involvement of central and peripheral type benzodiazepine binding sites. Pharmacol Toxicol. 1990 Jan;66(1):41-4. DOI: 10.1111/j.1600-0773.1990.tb00699.x. PMID: 2155416.

Kimura H. Production and physiological effects of hydrogen sulfide. Antioxid Redox Signal. 2014 Feb 10;20(5):783-93. DOI: 10.1089/ars.2013.5309. Epub 2013 May 25. PMID: 23581969; PMCID: PMC3910667.

Lapin I. Phenibut (beta-phenyl-GABA): A tranquilizer and nootropic drug. CNS Drug Rev. 2001 Winter;7(4):471-81. DOI: 10.1111/j.1527-3458.2001.tb00211.x. PMID: 11830761; PMCID: PMC6494145.

Grinberga S, Zvejniece L, Liepinsh E, Dambrova M, Pugovics O. Quantitative analysis of phenibut in rat brain tissue extracts by liquid chromatography-tandem mass spectrometry. Biomed Chromatogr. 2008 Dec;22(12):1321-4. DOI: 10.1002/bmc.1059. PMID: 19034959.

Owen DR, Wood DM, Archer JR, Dargan PI. Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity. Drug Alcohol Rev. 2016 Sep;35(5):591-6. DOI: 10.1111/dar.12356. Epub 2015 Dec 23. PMID: 26693960.

Maslova MN, Khaunina RA Penetration of gamma-aminobutyric acid and its phenyl derivative into the brain and their pharmacological effects in mice and rats during ontogenesis. Evol Neirofiziol Neirokhim. 1967;5:186–191.

Dambrova M, Zvejniece L, Liepinsh E, Cirule H, Zharkova O, Veinberg G, Kalvinsh I. Comparative pharmacological activity of optical isomers of phenibut. Eur J Pharmacol. 2008 Mar 31;583(1):128-34.

DOI: 10.1016/j.ejphar.2008.01.015. Epub 2008 Jan 26. PMID: 18275958.

Morley KC, Baillie A, Leung S, Addolorato G, Leggio L, Haber PS. Baclofen for the Treatment of Alcohol Dependence and Possible Role of Comorbid Anxiety. Alcohol Alcohol. 2014 Nov;49(6):654-60. DOI: 10.1093/alcalc/agu062. Epub 2014 Sep 21. PMID: 25246489; PMCID: PMC4804107.

Kukkar A, Bali A, Singh N, Jaggi AS. Implications and mechanism of action of gabapentin in neuropathic pain. Arch Pharm Res. 2013 Mar;36(3):237-51. DOI: 10.1007/s12272-013-0057-y. Epub 2013 Feb 24. PMID: 23435945.

Buu NT, Van Gelder NM. Biological actions in vivo and in vitro of two gamma-aminobutyric acid (GABA) analogues: Beta-chloro GABA and beta-phenyl GABA. Br J Pharmacol. 1974 Nov; 52(3):401-6.

DOI: 10.1111/j.1476-5381.1974.tb08609.x. PMID: 4156485; PMCID: PMC1777036.

Davies J, Watkins JC. The action of beta-phenyl-GABA derivatives on neurones of the cat cerebral cortex. Brain Res. 1974 Apr 26;70(3):501-5. DOI: 10.1016/0006-8993(74)90258-3. PMID: 4821062.

Irie T, Yamazaki D, Kikura-Hanajiri R. F-phenibut (β-(4-Fluorophenyl)-GABA), a potent GABAB receptor agonist, activates an outward-rectifying K+ current and suppresses the generation of action potentials in mouse cerebellar Purkinje cells. Eur J Pharmacol. 2020 Oct 5;884:173437.

DOI: 10.1016/j.ejphar.2020.173437. Epub 2020 Jul 28. PMID: 32735986.

Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, Kalvinsh I, Dambrova M. R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects. Pharmacol Biochem Behav. 2015 Oct;137:23-9. DOI: 10.1016/j.pbb.2015.07.014. Epub 2015 Jul 31. PMID: 26234470.

Jackson MR, Melideo SL, Jorns MS. Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry. 2012 Aug 28;51(34):6804-15. DOI: 10.1021/bi300778t. Epub 2012 Aug 20. PMID: 22852582.

Gadalla MM, Snyder SH. Hydrogen sulfide as a gasotransmitter. J Neurochem. 2010 Apr;113(1):14-26.

DOI: 10.1111/j.1471-4159.2010.06580.x. Epub 2010 Jan 12. PMID: 20067586; PMCID: PMC2965526.

Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids. 2011 Jun;41(1):113-21.

DOI: 10.1007/s00726-010-0510-x. Epub 2010 Feb 27. PMID: 20191298.

Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 2002 Nov;16(13):1792-8. DOI: 10.1096/fj.02-0211hyp. PMID: 12409322.

Cuevasanta E, Denicola A, Alvarez B, Möller MN. Solubility and permeation of hydrogen sulfide in lipid membranes. PLoS One. 2012;7(4):e34562. DOI: 10.1371/journal.pone.0034562. Epub 2012 Apr 11. PMID: 22509322; PMCID: PMC3324494.

Shibuya N, Kimura H. Production of hydrogen sulfide from d-cysteine and its therapeutic potential. Front Endocrinol (Lausanne). 2013 Jul 16;4:87.

DOI: 10.3389/fendo.2013.00087. PMID: 23882260; PMCID: PMC3712494.

Cai H, Wang X. Effect of sulfur dioxide on vascular biology. Histol Histopathol. 2021 May;36(5):505-514.

DOI: 10.14670/HH-18-290. Epub 2020 Dec 15. PMID: 33319344.

Whiteman M, Le Trionnaire S, Chopra M, Fox B, Whatmore J. Emerging role of hydrogen sulfide in health and disease: critical appraisal of biomarkers and pharmacological tools. Clin Sci (Lond). 2011 Dec;121(11):459-88. DOI: 10.1042/CS20110267. PMID: 21843150.

Xiao Q, Ying J, Xiang L, Zhang C. The biologic effect of hydrogen sulfide and its function in various diseases. Medicine (Baltimore). 2018 Nov;97(44):e13065. DOI: 10.1097/MD.0000000000013065. PMID: 30383685; PMCID: PMC6221678.

Bhatia M, Wong FL, Fu D, Lau HY, Moochhala SM, Moore PK. Role of hydrogen sulfide in acute pancreatitis and associated lung injury. FASEB J. 2005 Apr;19(6):623-5. DOI: 10.1096/fj.04-3023fje. Epub 2005 Jan 25. Erratum in: FASEB J. 2005 Apr;19(6):2 p following 625. PMID: 15671155.

Bhatia M, Gaddam RR. Hydrogen Sulfide in Inflammation: A Novel Mediator and Therapeutic Target. Antioxid Redox Signal. 2021 Jun 10;34(17):1368-1377. DOI: 10.1089/ars.2020.8211. Epub 2020 Dec 2. PMID: 33138636.

Zhou Y, Li XH, Zhang CC, Wang MJ, Xue WL, Wu DD, Ma FF, Li WW, Tao BB, Zhu YC. Hydrogen sulfide promotes angiogenesis by downregulating miR-640 via the VEGFR2/mTOR pathway. Am J Physiol Cell Physiol. 2016 Feb 15;310(4):C305-17. DOI: 10.1152/ajpcell.00230.2015. Epub 2015 Nov 25. PMID: 26879375.

Chen WL, Xie B, Zhang C, Xu KL, Niu YY, Tang XQ, Zhang P, Zou W, Hu B, Tian Y. Antidepressant-like and anxiolytic-like effects of hydrogen sulfide in behavioral models of depression and anxiety. Behav Pharmacol. 2013 Oct;24(7): 590-7. DOI: 10.1097/FBP.0b013e3283654258. PMID: 23974423.

Dutta SS, Dasgupta S, Banerjee AK, Nath I, Biswas U, Bera N, Ruram A. Exploring the Role of Serum Hydrogen Sulphide (H2S) Levels in Manic Depressive Psychosis in Terms of Its Association, Diagnostic Ability, and Severity Prediction: Findings From a Tertiary Care Center in North Bengal. Cureus. 2024 Mar 24;16(3):e56857. DOI: 10.7759/cureus.56857. PMID: 38659549; PMCID: PMC11040162.

Kang X, Jiang L, Lan F, Tang YY, Zhang P, Zou W, Chen YJ, Tang XQ. Hydrogen sulfide antagonizes sleep deprivation-induced depression- and anxiety-like behaviors by inhibiting neuroinflammation in a hippocampal Sirt1-dependent manner. Brain Res Bull. 2021 Dec;177:194- 202.

DOI: 10.1016/j.brainresbull.2021.10.002. Epub 2021 Oct 5. PMID: 34624463.

Rodkin S, Nwosu C, Sannikov A, Raevskaya M, Tushev A, Vasilieva I, Gasanov M. The Role of Hydrogen Sulfide in Regulation of Cell Death following Neurotrauma and Related Neurodegenerative and Psychiatric Diseases. Int J Mol Sci. 2023 Jun 28;24(13):10742. DOI: 10.3390/ijms241310742. PMID: 37445920; PMCID: PMC10341618.

Yang YJ, Chen CN, Zhan JQ, Liu QS, Liu Y, Jiang SZ, Wei B. Decreased Plasma Hydrogen Sulfide Level Is Associated With the Severity of Depression in Patients With Depressive Disorder. Front Psychiatry. 2021 Nov 11;12:765664. DOI: 10.3389/fpsyt.2021.765664. PMID: 34858235; PMCID: PMC8631961.

Sakai K, Katsumi H, Sugiura M, Tamba A, Kamano K, Yamauchi K, Tamura Y, Sakane T, Yamamoto A. Pharmacokinetics and Preventive Effects of Sulfo-Albumin as a Novel Macromolecular Hydrogen Sulfide Prodrug on Carbon Tetrachloride-Induced Hepatic Injury. J Pharm Sci. 2018 Oct;107(10):2686-2693.

DOI: 10.1016/j.xphs.2018.06.022. Epub 2018 Jul 2. PMID: 30156185.

Zaorska E, Tomasova L, Koszelewski D, Ostaszewski R, Ufnal M. Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors. Biomolecules. 2020 Feb 18;10(2):323.

DOI: 10.3390/biom10020323. PMID: 32085474 PMCID: PMC7072623.