Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Tolerability and pharmacokinetics of ginsenosides Rb1, Rb2, Rc, Rd, and compound K after single or multiple administration of red ginseng extract in human beings

  • Choi, Min-Koo (College of Pharmacy, Dankook University) ;
  • Jin, Sojeong (College of Pharmacy, Dankook University) ;
  • Jeon, Ji-Hyeon (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Kyungpook National University) ;
  • Kang, Woo Youl (Clinical Trial Center, Kyungpook National University Hospital) ;
  • Seong, Sook Jin (Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, Graduate School, Kyungpook National University) ;
  • Yoon, Young-Ran (Clinical Trial Center, Kyungpook National University Hospital) ;
  • Han, Yong-Hae (Life Science Institute, Daewoong Pharmaceutical) ;
  • Song, Im-Sook (Research Institute of Pharmaceutical Sciences and College of Pharmacy, Kyungpook National University)
  • Received : 2018.06.20
  • Accepted : 2018.10.18
  • Published : 2020.03.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: We investigated the tolerability and pharmacokinetic properties of various ginsenosides, including Rb1, Rb2, Rc, Rd, and compound K, after single or multiple administrations of red ginseng extract in human beings. Methods: Red ginseng extract (dried ginseng > 60%) was administered once and repeatedly for 15 days to 15 healthy Korean people. After single and repeated administration of red ginsengextract, blood sample collection, measurement of blood pressure and body temperature, and routine laboratory test were conducted over 48-h test periods. Results: Repeated administration of high-dose red ginseng for 15 days was well tolerated and did not produce significant changes in body temperature or blood pressure. The plasma concentrations of Rb1, Rb2, and Rc were stable and showed similar area under the plasma concentration-time curve (AUC) values after 15 days of repeated administration. Their AUC values after repeated administration of red ginseng extract for 15 days accumulated 4.5- to 6.7-fold compared with single-dose AUC. However, the plasma concentrations of Rd and compound K showed large interindividual variations but correlated well between AUC of Rd and compound K. Compound K did not accumulate after 15 days of repeated administration of red ginseng extract. Conclusion: A good correlation between the AUC values of Rd and compound K might be the result of intestinal biotransformation of Rb1, Rb2, and Rc to Rd and subsequently to compound K, rather than the intestinal permeability of these ginsenosides. A strategy to increase biotransformation or reduce metabolic intersubject variability may increase the plasma concentrations of Rd and compound K.

Keywords

References

  1. Choi KT. Botanical characteristics, pharmacological effects and medicinal components of korean panax ginseng c a meyer. Acta Pharmacol Sin 2008;29:1109-18. https://doi.org/10.1111/j.1745-7254.2008.00869.x
  2. Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. Characterization of korean red ginseng (panax ginseng meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91. https://doi.org/10.1016/j.jgr.2015.04.009
  3. Kim MG, Kim Y, Jeon JY, Kim DS. Effect of fermented red ginseng on cytochrome p450 and p-glycoprotein activity in healthy subjects, as evaluated using the cocktail approach. Br J Clin Pharmacol 2016;82:1580-90. https://doi.org/10.1111/bcp.13080
  4. Ru W, Wang D, Xu Y, He X, Sun YE, Qian L, Zhou X, Qin Y. Chemical constituents and bioactivities of panax ginseng (c. A. Mey.). Drug Discov Ther 2015;9:23-32. https://doi.org/10.5582/ddt.2015.01004
  5. Kim JH, Yi YS, Kim MY, Cho JY. Role of ginsenosides, the main active components of panax ginseng, in inflammatory responses and diseases. J Ginseng Res 2017;41:435-43. https://doi.org/10.1016/j.jgr.2016.08.004
  6. Yun TK, Choi SY, Yun HY. Epidemiological study on cancer prevention by ginseng: are all kinds of cancers preventable by ginseng? J Korean Med Sci 2001;16(Suppl):S19-27. https://doi.org/10.3346/jkms.2001.16.S.S19
  7. Gui QF, Xu ZR, Xu KY, Yang YM. The efficacy of ginseng-related therapies in type 2 diabetes mellitus: an updated systematic review and meta-analysis. Medicine (Baltimore) 2016;95:e2584. https://doi.org/10.1097/md.0000000000002584
  8. Park TY, Hong M, Sung H, Kim S, Suk KT. Effect of korean red ginseng in chronic liver disease. J Ginseng Res 2017;41:450-5. https://doi.org/10.1016/j.jgr.2016.11.004
  9. Choi ID, Ryu JH, Lee DE, Lee MH, Shim JJ, Ahn YT, Sim JH, Huh CS, Shim WS, Yim SV, et al. Enhanced absorption study of ginsenoside compound k (20-obeta-( d-glucopyranosyl)-20(s)-protopanaxadiol) after oral administration of fermented red ginseng extract (hyfrg) in healthy korean volunteers and rats. Evid Base Compl Alternat Med 2016;2016:3908142.
  10. Odani T, Tanizawa H, Takino Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. Iv. Decomposition of ginsenoside-rg1 and -rb1 in the digestive tract of rats. Chem Pharm Bull (Tokyo) 1983;31:3691-7. https://doi.org/10.1248/cpb.31.3691
  11. Xu QF, Fang XL, Chen DF. Pharmacokinetics and bioavailability of ginsenoside rb1 and rg1 from panax notoginseng in rats. J Ethnopharmacol 2003;84:187-92. https://doi.org/10.1016/S0378-8741(02)00317-3
  12. Liu H, Yang J, Du F, Gao X, Ma X, Huang Y, Xu F, Niu W, Wang E, Mao Y, et al. Absorption and disposition of ginsenosides after oral administration of panax notoginseng extract to rats. Drug Metab Dispos 2009;37:2290-8. https://doi.org/10.1124/dmd.109.029819
  13. Kim HK. Pharmacokinetics of ginsenoside rb1 and its metabolite compound k after oral administration of korean red ginseng extract. J Ginseng Res 2013;37:451-6. https://doi.org/10.5142/jgr.2013.37.451
  14. Akao T, Kida H, Kanaoka M, Hattori M, Kobashi K. Intestinal bacterial hydrolysis is required for the appearance of compound k in rat plasma after oral administration of ginsenoside rb1 from panax ginseng. J Pharm Pharmacol 1998;50:1155-60. https://doi.org/10.1111/j.2042-7158.1998.tb03327.x
  15. Lee J, Lee E, Kim D, Lee J, Yoo J, Koh B. Studies on absorption, distribution and metabolism of ginseng in humans after oral administration. J Ethnopharmacol 2009;122:143-8. https://doi.org/10.1016/j.jep.2008.12.012
  16. Choi MK, Song IS. Characterization of efflux transport of the pde5 inhibitors, vardenafil and sildenafil. J Pharm Pharmacol 2012;64:1074-83. https://doi.org/10.1111/j.2042-7158.2012.01498.x
  17. Choi YA, Yoon YH, Choi K, Kwon M, Goo SH, Cha JS, Choi MK, Song IS. Enhanced oral bioavailability of morin administered in mixed micelle formulation with pluronicf127 and tween80 in rats. Biol Pharm Bull 2015;38:208-17. https://doi.org/10.1248/bpb.b14-00508
  18. Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31:1065-71. https://doi.org/10.1124/dmd.31.8.1065
  19. Zheng MM, Xu FX, Li YJ, Xi XZ, Cui XW, Han CC, Zhang XL. Study on transformation of ginsenosides in different methods. Biomed Res Int 2017;2017:8601027.
  20. Qian T, Cai Z. Biotransformation of ginsenosides rb1, rg3 and rh2 in rat gastrointestinal tracts. Chin Med 2010;5:19. https://doi.org/10.3760/cma.j.issn.1673-4777.2010.13.009
  21. Park SE, Na CS, Yoo SA, Seo SH, Son HS. Biotransformation of major ginsenosides in ginsenoside model culture by lactic acid bacteria. J Ginseng Res 2017;41:36-42. https://doi.org/10.1016/j.jgr.2015.12.008
  22. Kang A, Zhang S, Zhu D, Dong Y, Shan J, Xie T, Wen H, Di L. Gut microbiota in the pharmacokinetics and colonic deglycosylation metabolism of ginsenoside rb1 in rats: contrary effects of antimicrobials treatment and restraint stress. Chem Biol Interact 2016;258:187-96. https://doi.org/10.1016/j.cbi.2016.09.005
  23. Christensen LP. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res 2009;55:1-99. https://doi.org/10.1016/S1043-4526(08)00401-4
  24. Kang KS, Kim HY, Yamabe N, Nagai R, Yokozawa T. Protective effect of sun ginseng against diabetic renal damage. Biol Pharm Bull 2006;29:1678-84. https://doi.org/10.1248/bpb.29.1678
  25. Hasegawa H, Sung JH, Benno Y. Role of human intestinal prevotella oris in hydrolyzing ginseng saponins. Planta Med 1997;63:436-40. https://doi.org/10.1055/s-2006-957729
  26. Miyamoto E, Odashima S, Kitagawa I, Tsuji A. Stability kinetics of ginsenosides in aqueous solution. J Pharm Sci 1984;73:409-10. https://doi.org/10.1002/jps.2600730334
  27. Kim DS, Kim Y, Jeon JY, Kim MG. Effect of red ginseng on cytochrome p450 and p-glycoprotein activities in healthy volunteers. J Ginseng Res 2016;40:375-81. https://doi.org/10.1016/j.jgr.2015.11.005
  28. Malati CY, Robertson SM, Hunt JD, Chairez C, Alfaro RM, Kovacs JA, Penzak SR. Influence of panax ginseng on cytochrome p450 (cyp)3a and p-glycoprotein (p-gp) activity in healthy participants. J Clin Pharmacol 2012;52:932-9. https://doi.org/10.1177/0091270011407194
  29. Kim JH, Pan JH, Cho HT, Kim YJ. Black ginseng extract counteracts streptozotocin-induced diabetes in mice. PLoS One 2016;11, e0146843. https://doi.org/10.1371/journal.pone.0146843
  30. Bang H, Kwak JH, Ahn HY, Shin DY, Lee JH. Korean red ginseng improves glucose control in subjects with impaired fasting glucose, impaired glucose tolerance, or newly diagnosed type 2 diabetes mellitus. J Med Food 2014;17:128-34. https://doi.org/10.1089/jmf.2013.2889

Cited by

  1. Detection of 13 Ginsenosides (Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, Compound K, 20(S)-Protopanaxadiol, and 20(S)-Protopanaxatriol) in Human Plasma and Application of the Analytical Method to Hu vol.24, pp.14, 2019, https://doi.org/10.3390/molecules24142618
  2. Herb–Drug Interaction of Red Ginseng Extract and Ginsenoside Rc with Valsartan in Rats vol.25, pp.3, 2020, https://doi.org/10.3390/molecules25030622
  3. Pharmacokinetics and Intestinal Metabolism of Compound K in Rats and Mice vol.12, pp.2, 2020, https://doi.org/10.3390/pharmaceutics12020129
  4. Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities vol.10, pp.7, 2020, https://doi.org/10.3390/biom10071028
  5. Immunomodulatory drug discovery from herbal medicines: Insights from organ-specific activity and xenobiotic defenses vol.10, 2020, https://doi.org/10.7554/elife.73673
  6. Correlation between the Content and Pharmacokinetics of Ginsenosides from Four Different Preparation of Panax Ginseng C.A. Meyer in Rats vol.12, pp.1, 2021, https://doi.org/10.5478/msl.2021.12.1.16
  7. Improved Hygroscopicity and Bioavailability of Solid Dispersion of Red Ginseng Extract with Silicon Dioxide vol.13, pp.7, 2020, https://doi.org/10.3390/pharmaceutics13071022
  8. Rh2-enriched Korean ginseng (Ginseng Rh2+) inhibits tumor growth and development of metastasis of non-small cell lung cancer vol.12, pp.17, 2020, https://doi.org/10.1039/d1fo00643f
  9. Effect of Lactic Acid Bacteria on the Pharmacokinetics and Metabolism of Ginsenosides in Mice vol.13, pp.9, 2020, https://doi.org/10.3390/pharmaceutics13091496
  10. In vitro modulatory effects of ginsenoside compound K, 20(S)-protopanaxadiol and 20(S)-protopanaxatriol on uridine 5′-diphospho-glucuronosyltransferase activity and expression vol.51, pp.10, 2020, https://doi.org/10.1080/00498254.2021.1963503
  11. Development of a Sensitive Analytical Method of Polynemoraline C Using LC-MS/MS and Its Application to a Pharmacokinetic Study in Mice vol.12, pp.4, 2021, https://doi.org/10.5478/msl.2021.12.4.200