Pharmacokinetics and pharmacodynamics of rebamipide. New possibilities of therapy: A review

Cover Page

Cite item

Full Text

Abstract

The MedLine database contains 570 publications, including 71 randomized clinical trials and 6 meta-analyses on the rebamipide molecule in 2022. Indications for the use of rebamipide are gastric ulcer, chronic gastritis with hyperacidityin the acute stage, erosive gastritis, prevention of damage to the gastrointestinal mucosa while taking non-steroidal anti-inflammatory drugs, eradication of Helicobacter pylori. Currently trials are studying the efficacy and safety of the drug in gouty and rheumatoid arthritis, osteoarthritis, Sjögren's syndrome, bronchial asthma, vitiligo, atherosclerosis, diseases of the kidneys and liver; using in traumatology to accelerate bone regeneration; in ophthalmology to improve the regeneration of corneal epithelium; in oncology to reduce inflammatory changes in the oral mucosa after chemoradiotherapy. The review article is about the main pharmacokinetic and pharmacodynamic characteristics of rebamipide. A detailed understanding of pharmacodynamics and pharmacokinetics allows for individual selection of therapy based on the characteristics of the patient's body – gender, age, comorbidities; choose the optimal route of administration and dosing regimen; predict adverse effects and drug interactions; be determined with new clinical indications.

About the authors

Natalia V. Bakulina

Mechnikov North-Western State Medical University

Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0003-4075-4096

д-р мед. наук, зав. каф. внутренних болезней, клинической фармакологии и нефрологии ФГБОУ ВО «СЗГМУ им. И.И. Мечникова»

Russian Federation, Saint Petersburg

Sergey V. Tikhonov

Mechnikov North-Western State Medical University

Author for correspondence.
Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0001-5720-3528

канд. мед. наук, доц. каф. внутренних болезней, клинической фармакологии и нефрологии ФГБОУ ВО «СЗГМУ им. И.И. Мечникова»

Russian Federation, Saint Petersburg

Sergey V. Okovityi

Saint Petersburg State Chemical Pharmaceutical University

Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0003-4294-5531

д-р мед. наук, проф., зав. каф. фармакологии и клинической фармакологии ФГБОУ ВО СПХФУ

Russian Federation, Saint Petersburg

Elena A. Lutaenko

Mechnikov North-Western State Medical University

Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0003-3472-3728

канд. мед. наук, доц. каф. внутренних болезней, клинической фармакологии и нефрологии ФГБОУ ВО «СЗГМУ им. И.И. Мечникова»

Russian Federation, Saint Petersburg

Alexandеr O. Bolshakov

Mechnikov North-Western State Medical University

Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0002-5103-5778

ординатор каф. внутренних болезней, клинической фармакологии и нефрологии ФГБОУ ВО «СЗГМУ им. И.И. Мечникова»

Russian Federation, Saint Petersburg

Veronika A. Prikhodko

Saint Petersburg State Chemical Pharmaceutical University

Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0002-4690-1811

ассистент каф. фармакологии и клинической фармакологии ФГБОУ ВО СПХФУ

Russian Federation, Saint Petersburg

Anna S. Nekrasova

Mechnikov North-Western State Medical University

Email: sergeyvt2702@gmail.com
ORCID iD: 0000-0001-5198-9902

канд. мед. наук, доц. каф. внутренних болезней, клинической фармакологии и нефрологии ФГБОУ ВО «СЗГМУ им. И.И. Мечникова»

Russian Federation, Saint Petersburg

References

  1. Uchida M, Tabusa F, Komatsu M, et al. Studies on 2(1H) – quinolinone derivatives as gastric antiulcer active agents. 2-(4-Chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid and related compounds. Chem Pharm Bull (Tokyo). 1985;33(9):3775-86. doi: 10.1248/cpb.33.3775
  2. Ogino K, Hobara T, Ishiyama H, et al. Antiulcer mechanism of action of rebamipide, a novel antiulcer compound, on diethyldithiocarbamate-induced antral gastric ulcers in rats. Eur J Pharmacol. 1992;212(1):9-13. doi: 10.1016/0014-2999(92)90065-c
  3. Arakawa T, Kobayashi K, Yoshikawa T, et al. Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing. Dig Dis Sci. 1998;43(9 Suppl.):5S-13S.
  4. Suzuki M, Miura S, Mori M, et al. Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut. 1994;35(10):1375-8. doi: 10.1136/gut.35.10.1375
  5. Кукес В.Г. Фармакоэкономический анализ. В кн.: Клиническая фармакология: учебник. Под ред. Д.А. Сычева. 5-е изд., испр. и доп. М.: ГЭОТАР-Медиа, 2017; с. 80-7 [Kukes VG. Farmakoekonomicheskii analis. V kn.: Klinicheskaia farmakologiia: uchebnik. Pod red. DA Sycheva. 5-e izd., ispr. i dop. Moscow: GEOTAR-Media, 2017; р. 80-7 (in Russian)].
  6. Murata H, Yabe Y, Tsuji S, et al. Gastro-protective agent rebamipide induces cyclooxygenease-2 (COX-2) in gastric epithelial cells. Dig Dis Sci. 2005;50 (Suppl. 1):S70-5. doi: 10.1007/s10620-005-2809-0
  7. Lee S, Jeong S, Kim W, et al. Rebamipide induces the gastric mucosal protective factor, cyclooxygenase-2, via activation of 5’-AMP-activated protein kinase. Biochem Biophys Res Commun. 2017;483(1):449-55. doi: 10.1016/j.bbrc.2016.12.123
  8. Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells [published correction appears in Nat Med. 2015 Apr;21(4):414]. Nat Med. 2014;20(11):1327-33. doi: 10.1038/nm.3704
  9. Agard M, Asakrah S, Morici LA. PGE(2) suppression of innate immunity during mucosal bacterial infection. Front Cell Infect Microbiol. 2013;3:45. doi: 10.3389/fcimb.2013.00045
  10. Katada K, Yoshida N, Isozaki Y, et al. Prevention by rebamipide of acute reflux esophagitis in rats. Dig Dis Sci. 2005;(50 Suppl.)1:S97-103. doi: 10.1007/s10620-005-2813-4
  11. Yamane S, Amano H, Ito Y, et al. The role of thromboxane prostanoid receptor signaling in gastric ulcer healing. Int J Exp Pathol. 2022;103(1):4-12. doi: 10.1111/iep.12410
  12. Ishihara T, Suemasu S, Asano T, et al. Stimulation of gastric ulcer healing by heat shock protein 70. Biochem Pharmacol. 2011;82(7):728-36. doi: 10.1016/j.bcp.2011.06.030
  13. Suzuki T, Yoshida N, Nakabe N, et al. Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci. 2008;106(3):469-77. doi: 10.1254/jphs.FP0071422
  14. Tanaka H, Fukuda K, Ishida W, et al. Rebamipide increases barrier function and attenuates TNFα-induced barrier disruption and cytokine expression in human corneal epithelial cells. Br J Ophthalmol. 2013;97(7):912-6. doi: 10.1136/bjophthalmol-2012-302868
  15. Андреев Д.Н., Маев И.В. Ребамипид: доказательная база применения в гастроэнтерологии. Терапевтический архив. 2020;92(12)97-104 [Andreev DN, Maev IV. Rebamipide: evidence base for use in gastroenterology. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(12)97-104 (in Russian)]. doi: 10.26442/00403660.2020.12.200455
  16. Ивашкин В.Т., Трухманов А.С., Гоник М.И. Применение ребамипида в лечении гастроэзофагеальной рефлюксной болезни. Терапевтический архив. 2020;92(4):98-104 [Ivashkin VT, Trukhmanov AS, Gonik MI. Rebamipide using in gastroesophageal reflux disease treatment. Terapevticheskii Arkhiv (Ter. Arkh.). 2020;92(4):98-104 (in Russian)]. doi: 10.26442/00403660.2020.04.000568
  17. Парфенов А.И., Белостоцкий Н.И., Хомерики С.Г., и др. Ребамипид повышает активность дисахаридаз у больных энтеропатией с нарушением мембранного пищеварения. Пилотное исследование. Терапевтический архив. 2019;91(2):25-31 [Parfenov AI, Belostotsky NI, Khomeriki SG, et al. Rebamipide increases the disaccharidases activity in patients with enteropathy with impaired membrane digestion. Pilot study. Terapevticheskii Arkhiv (Ter. Arkh.). 2019;91(2):25-31 (in Russian)]. doi: 10.26442/00403660.2019.02.000123
  18. Tanigawa T, Watanabe T, Higashimori A, et al. Rebamipide ameliorates indomethacin-induced small intestinal damage and proton pump inhibitor-induced exacerbation of this damage by modulation of small intestinal microbiota. PloS One. 2021;16(1):e0245995. doi: 10.1371/journal.pone.0245995
  19. Симаненков В.И., Тихонов С.В. Ребамипид – новые возможности гастропротекции. Терапевтический архив. 2015;87(12):134-7 [Simanenkov VI, Tikhonov SV. Rebamipide: New opportunities of gastroenteroprotection. Terapevticheskii Arkhiv (Ter. Arkh.). 2015;87(12):134-7 (in Russian)]. doi: 10.17116/terarkh20158712134-137
  20. Lai Y, Zhong W, Yu T, et al. Rebamipide Promotes the Regeneration of Aspirin-Induced Small-Intestine Mucosal Injury through Accumulation of β-Catenin. PloS One. 2015;10(7):e0132031. doi: 10.1371/journal.pone.0132031
  21. Chiurillo MA. Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review. World J Exp Med. 2015;5(2):84-102. doi: 10.5493/wjem.v5.i2.84
  22. White BD, Chien AJ, Dawson DW. Dysregulation of Wnt/β-catenin signaling in gastrointestinal cancers. Gastroenterology. 2012;142(2):219-32. doi: 10.1053/j.gastro.2011.12.001
  23. Byun JK, Moon SJ, Jhun JY, et al. Rebamipide attenuates autoimmune arthritis severity in SKG mice via regulation of B cell and antibody production. Clin Exp Immunol. 2014;178(1):9-19. doi: 10.1111/cei.12355
  24. Zakaria S, El-Sisi A. Rebamipide retards CCl4-induced hepatic fibrosis in rats: Possible role for PGE2. J Immunotoxicol. 2016;13(4):453-62. doi: 10.3109/1547691X.2015.1128022
  25. Lee SM, Kim KH. Rebamipide ameliorates hepatic dysfunction induced by ischemia/reperfusion in rats. Eur J Pharmacol. 1995;294(1):41-6. doi: 10.1016/0014-2999(95)00507-2
  26. Elmansy RA, Seleem HS, Mahmoud AR, et al. Rebamipide potentially mitigates methotrexate-induced nephrotoxicity via inhibition of oxidative stress and inflammation: A molecular and histochemical study. Anat Rec (Hoboken). 2021;304(3):647-61. doi: 10.1002/ar.24482
  27. Arakaki R, Eguchi H, Yamada A, et al. Anti-inflammatory effects of rebamipide eyedrop administration on ocular lesions in a murine model of primary Sjögren’s syndrome. PloS One. 2014;9(5):e98390. doi: 10.1371/journal.pone.0098390
  28. Кукес В.Г. Фармакоэкономический анализ. В кн.: Клиническая фармакология: учебник. Под ред. Д.А. Сычева. 5-е изд., испр. и доп. М.: ГЭОТАР-Медиа, 2017; с. 56 [Kukes VG. Farmakoekonomicheskii analis. V kn.: Klinicheskaia farmakologiia: uchebnik. Pod red. DA Sycheva. 5-e izd., ispr. i dop. Moscow: GEOTAR-Media, 2017; р. 56 (in Russian)].
  29. Currie GM. Pharmacology, Part 2: Introduction to Pharmacokinetics. J Nucl Med Technol. 2018;46(3):221-30. doi: 10.2967/jnmt.117.199638
  30. Кукес В.Г. Фармакоэкономический анализ. В кн.: Клиническая фармакология: учебник. Под ред. Д.А. Сычева. 5-е изд., испр. и доп. М.: ГЭОТАР-Медиа, 2017; с. 22-36 [Kukes VG. Farmakoekonomicheskii analis. V kn.: Klinicheskaia farmakologiia: uchebnik. Pod red. DA Sycheva. 5-e izd., ispr. i dop. Moscow: GEOTAR-Media, 2017; р. 22-36 (in Russian)].
  31. Ngo L, Yoo HD, Tran P, et al. Population pharmacokinetic analysis of rebamipide in healthy Korean subjects with the characterization of atypical complex absorption kinetics. J Pharmacokinet Pharmacodyn. 2017;44(4):291-303. doi: 10.1007/s10928-017-9519-z
  32. Guo Y, Wang Y, Xu L. Enhanced bioavailability of rebamipide nanocrystal tablets: formulation and in vitro/in vivo evaluation. Asian J Pharm Sci. 2015;10:223-9. doi: 10.1016/j.ajps.2014.09.006
  33. Pond SM, Tozer TN. First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet. 1984;9(1):1-25. doi: 10.2165/00003088-198409010-00001
  34. Bhosle VK, Altit G, Autmizguine J, Chemtob S. 18 – Basic Pharmacologic Principles. Eds. RA Polin, SH Abman, DH Rowitch, et al. Fetal and Neonatal Physiology (Fifth Edition). Elsevier, 2017.
  35. Kim KT, Lee JY, Park JH, et al. Capmul MCM/Solutol HS15-Based Microemulsion for Enhanced Oral Bioavailability of Rebamipide. J Nanosci Nanotechnol. 2017;17(4):2340-4. DOI:10.1166/ jnn.2017.13314
  36. Hasegawa S, Sekino H, Matsuoka O, et al. Bioequivalence of rebamipide granules and tablets in healthy adult male volunteers. Clin Drug Investig. 2003;23(12):771-9. doi: 10.2165/00044011-200323120-00002
  37. Naito Y, Yoshikawa T. Rebamipide: a gastrointestinal protective drug with pleiotropic activities. Exp Rev Gastroenterol Hepatol. 2010;4(3):261-70. doi: 10.1586/egh.10.25
  38. Caldwell J, Gardner I, Swales N. An introduction to drug disposition: the basic principles of absorption, distribution, metabolism, and excretion. Toxicol Pathol. 1995;23(2):102-14. doi: 10.1177/019262339502300202
  39. Shioya Y, Shimizu T. High-performance liquid chromatographic procedure for the determination of a new anti-gastric ulcer agent, 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-ylv]propionic acid, in human plasma and urine. J Chromatogr A. 1988;434(1):283-7. doi: 10.1016/0378-4347(88)80089-6
  40. Park NC, Sim SB, Yan BQ, et al. The Antioxidant Effect of Rebamipide in Human Semen Specimens. Korean Journal of Urology. 2002:332-8.
  41. Patel M, Taskar KS, Zamek-Gliszczynski MJ. Importance of hepatic transporters in clinical disposition of drugs and their metabolites. J Clin Pharmacol. 2016;56(Suppl. 7):S23-39. doi: 10.1002/jcph.671
  42. Кукес В.Г. Фармакоэкономический анализ. В кн.: Клиническая фармакология: учебник. Под ред. Д.А. Сычева. 5-е изд., испр. и доп. М.: ГЭОТАР-Медиа, 2017; с. 75-8 [Kukes VG. Farmakoekonomicheskii analis. V kn.: Klinicheskaia farmakologiia: uchebnik. Pod red. DA Sycheva. 5-e izd., ispr. i dop. Moscow: GEOTAR-Media, 2017; р. 75-8 (in Russian)].
  43. Koyama N, Sasabe H, Miyamoto G. Involvement of cytochrome P450 in the metabolism of rebamipide by the human liver. Xenobiotica. 2002;32(7):573-86. doi: 10.1080/00498250210130591
  44. Lea-Henry TN, Carland JE, Stocker SL, et al. Clinical Pharmacokinetics in Kidney Disease: Fundamental Principles. Clin J Am Soc Nephrol. 2018;13(7):1085-95. doi: 10.2215/CJN.00340118
  45. Cho HY, Yoon H, Park GK, Lee YB. Pharmacokinetics and bioequivalence of two formulations of rebamipide 100-mg tablets: a randomized, single-dose, two-period, two-sequence crossover study in healthy Korean male volunteers. Clin Ther. 2009;31(11):2712-21. doi: 10.1016/j.clinthera.2009.11.010
  46. Jang E, Park M, Jeong JE, et al. Frequently reported adverse events of rebamipide compared to other drugs for peptic ulcer and gastroesophageal reflux disease. Sci Rep. 2022;12(1):7839. doi: 10.1038/s41598-022-11505-0
  47. Симаненков В.И., Маев И.В., Ткачева О.Н., и др. Синдром повышенной эпителиальной проницаемости в клинической практике. Мультидисциплинарный национальный консенсус. Кардиоваскулярная терапия и профилактика. 2021;20(1):121-278 [Simanenkov I, Maev IV, Tkacheva ON, et al. Syndrome of increased epithelial permeability in clinical practice. Multidisciplinary national Consensus. Cardiovascular Therapy and Prevention. 2021;20(1):121-278 (in Russian)]. doi: 10.15829/1728-8800-2021-2758
  48. Murakami I, Zhang R, Kubo M, et al. Rebamipide suppresses mite-induced asthmatic responses in NC/Nga mice. Am J Physiol Lung Cell Mol Physiol. 2015;309(8):L872-8. doi: 10.1152/ajplung.00194.2015
  49. Jhun JY, Kwon JE, Kim SY, et al. Rebamipide ameliorates atherosclerosis by controlling lipid metabolism and inflammation. PloS One. 2017;12(2):e0171674. doi: 10.1371/journal.pone.0171674
  50. Ohguchi T, Kojima T, Ibrahim O, et al. The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (sod1) knockout mice. Invest Ophthalmol Vis Sci. 2013;54(12):7793-802. doi: 10.1167/iovs.13-13128
  51. Ueta M, Sotozono Ch, Koga Ay, et al. Usefulness of a new therapy using rebamipide eyedrops in patients with VKC/AKC refractory to conventional anti-allergic treatments. Case Reports Allergol Int. 2014;63(1):75-81. doi: 10.2332/allergolint.13-OA-0605

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Chemical formula of the rebamipide molecule.

Download (44KB)
Indexing metadata
3. Fig. 2. Mechanism of prostaglandin synthesis and action of rebamipide.

Download (105KB)
Indexing metadata
4. Fig. 3. Pharmacokinetic curve of rebamipide after administration of 100 mg of the drug.

Download (64KB)
Indexing metadata

Copyright (c) 2022 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
 
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies