Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Effects of gut microbiota on the pharmacokinetics of protopanaxadiol ginsenosides Rd, Rg3, F2, and compound K in healthy volunteers treated orally with red ginseng

  • Kim, Jeon-Kyung (Neurobiota Research Center and Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University) ;
  • Choi, Min Sun (Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University) ;
  • Jeung, Woonhee (R&BD Center, Korea Yakult Co. Ltd.) ;
  • Ra, Jehyeon (R&BD Center, Korea Yakult Co. Ltd.) ;
  • Yoo, Hye Hyun (Institute of Pharmaceutical Science and Technology and College of Pharmacy, Hanyang University) ;
  • Kim, Dong-Hyun (Neurobiota Research Center and Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University)
  • Received : 2019.01.25
  • Accepted : 2019.05.29
  • Published : 2020.07.15
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Abstract

Background: It is well recognized that gut microbiota is involved in the biotransformation of ginsenosides by converting the polar ginsenosides to nonpolar bioactive ginsenosides. However, the roles of the gut microbiota on the pharmacokinetics of ginsenosides in humans have not yet been fully elucidated. Methods: Red ginseng (RG) or fermented red ginseng was orally administered to 34 healthy Korean volunteers, and the serum concentrations of the ginsenosides were determined using liquid chromatography-tandem mass spectrometry. In addition, the fecal ginsenoside Rd- and compound K (CK)eforming activities were measured. Then, the correlations between the pharmacokinetic profiles of the ginsenosides and the fecal ginsenoside-metabolizing activities were investigated. Results: For the RG group, the area under the serum concentratione-time curve values of ginsenosides Rd, F2, Rg3, and CK were 8.20 ± 11.95 ng·h/mL, 4.54 ± 3.70 ng·h/mL, 36.40 ± 19.68 ng·h/mL, and 40.30 ± 29.83 ng·h/mL, respectively. For the fermented red ginseng group, the the area under curve from zero to infinity (AUC∞) values of ginsenosides Rd, F2, Rg3, and CK were 187.90 ± 95.87 ng·h/mL, 30.24 ± 41.87 ng·h/mL, 28.68 ± 14.27 ng·h/mL, and 137.01 ± 96.16 ng·h/mL, respectively. The fecal CK-forming activities of the healthy volunteers were generally proportional to their ginsenoside Rd-eforming activities. The area under the serum concentration-time curve value of CK exhibited an obvious positive correlation (r = 0.566, p < 0.01) with the fecal CK-forming activity. Conclusion: The gut microbiota may play an important role in the bioavailability of the nonpolar RG ginsenosides by affecting the biotransformation of the ginsenosides.

Keywords

References

  1. 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
  2. Kim KH, Lee D, Lee HL, Kim CE, Jung K, Kang KS. Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. J Ginseng Res 2018;42:239-47. https://doi.org/10.1016/j.jgr.2017.03.011
  3. Li CP, Li RC. An introductory note to ginseng. Am J Chin Med 1973;1:249-61. https://doi.org/10.1142/S0192415X73000279
  4. Kasai R, Besso H, Tanaka O, Saruwatari Y, Fuwa T. Saponins of red ginseng. Chem Pharm Bull 1983;31:2120-5. https://doi.org/10.1248/cpb.31.2120
  5. 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
  6. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  7. Chang YS, Seo EK, Gyllenhaal C, Block KI. Panax ginseng: a role in cancer therapy? Integr Cancer Ther 2003;2:13-33. https://doi.org/10.1177/1534735403251167
  8. Helms S. Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev 2004;9:259-74.
  9. Joh EH, Lee IA, Jung IH, Kim DH. Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation-the key step of inflammation. Biochem Pharmacol 2011;82:278-86. https://doi.org/10.1016/j.bcp.2011.05.003
  10. Kim DH, Chung JH, Yoon JS, Ha YM, Bae S, Lee EK, Jung KJ, Kim MS, Kim YJ, Kim MK, et al. Ginsenoside Rd inhibits the expressions of iNOS and COX-2 by suppressing NF-kappaB in LPS-stimulated RAW264.7 cells and mouse liver. J Ginseng Res 2013;37:54-63. https://doi.org/10.5142/jgr.2013.37.54
  11. Yokozawa T, Kobayashi T, Oura H, Kawashima Y. Studies on the mechanism of the hypoglycemic activity of ginsenoside-Rb2 in streptozotocin-diabetic rats. Chem Pharm Bull 1985;33:869-72. https://doi.org/10.1248/cpb.33.869
  12. Bae EA, Park SY, Kim DH. Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull 2000;23:1481-5. https://doi.org/10.1248/bpb.23.1481
  13. Bae EA, Han MJ, Choo MK, Park SY, Kim DH. Metabolism of 20(S)- and 20(R)- ginsenoside Rg3 by human intestinal bacteria and its relation to in vitro biological activities. Biol Pharm Bull 2002;25:58-63. https://doi.org/10.1248/bpb.25.58
  14. Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH. Metabolism of ginsenoside R(c) by human intestinal bacteria and its related antiallergic activity. Biol Pharm Bull 2002;25:743-7. https://doi.org/10.1248/bpb.25.743
  15. Choi JR, Hong SW, Kim Y, Jang SE, Kim NJ, Han MJ, Kim DH. Metabolic activities of ginseng and its constituents, ginsenoside rb1 and rg1, by human intestinal microflora. J Ginseng Res 2011;35:301-7. https://doi.org/10.5142/jgr.2011.35.3.301
  16. Jung IH, Lee JH, Hyun YJ, Kim DH. Metabolism of ginsenoside Rb1 by human intestinal microflora and cloning of its metabolizing beta-D-glucosidase from Bifidobacterium longum H-1. Biol Pharm Bull 2012;35:573-81. https://doi.org/10.1248/bpb.35.573
  17. Kim DH. Metabolism of ginsenosides to bioactive compounds by intestinal microflora and its industrial application. J Ginseng Res 2009;33:165-76. https://doi.org/10.5142/JGR.2009.33.3.165
  18. Kim U, Park MH, Kim DH, Yoo HH. Metabolite profiling of ginsenoside Re in rat urine and faeces after oral administration. Food Chem 2013;136:1364-9. https://doi.org/10.1016/j.foodchem.2012.09.050
  19. Kim KA, Jung IH, Park SH, Ahn YT, Huh CS, Kim DH. Comparative analysis of the gut microbiota in people with different levels of ginsenoside Rb1 degradation to compound K. PLoS One 2013;8:e62409. https://doi.org/10.1371/journal.pone.0062409
  20. Kim JK, Kim JY, Jang SE, Choi MS, Jang HM, Yoo HH, Kim DH. Fermented red ginseng alleviates cyclophosphamide-induced immunosuppression and 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by regulating macrophage activation and T cell differentiation. Am J Chin Med 2018;46:1879-97. https://doi.org/10.1142/S0192415X18500945
  21. Kim DH. Gut microbiota-mediated pharmacokinetics of ginseng saponins. J Ginseng Res 2018;42:255-63. https://doi.org/10.1016/j.jgr.2017.04.011
  22. Wang HY, Hua HY, Liu XY, Liu JH, Yu BY. In vitro biotransformation of red ginseng extract by human intestinal microflora: metabolites identification and metabolic profile elucidation using LC-Q-TOF/MS. J Pharm Biomed Anal 2014;98:296-306. https://doi.org/10.1016/j.jpba.2014.06.006
  23. 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 Based Complement Alternat Med 2016;2016:3908142.
  24. Jin H, Seo JH, Uhm YK, Jung CY, Lee SK, Yim SV. Pharmacokinetic comparison of ginsenoside metabolite IH-901 from fermented and non-fermented ginseng in healthy Korean volunteers. J Ethnopharmacol 2012;139:664-7. https://doi.org/10.1016/j.jep.2011.11.052
  25. 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
  26. Kim JS, Kim Y, Han SH, Jeon JY, Hwang M, Im YJ, Kim JH, Lee SY, Chae SW, Kim MG. Development and validation of an LC-MS/MS method for determination of compound K in human plasma and clinical application. J Ginseng Res 2013;37:135-41. https://doi.org/10.5142/jgr.2013.37.135
  27. 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
  28. 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
  29. Saba E, Lee YY, Kim M, Kim SH, Hong SB, Rhee MH. A comparative study on immune-stimulatory and antioxidant activities of various types of ginseng extracts in murine and rodent models. Journal of Ginseng Research 2018;42:577-84. https://doi.org/10.1016/j.jgr.2018.07.004
  30. Yang XD, Yang YY, Ouyang DS, Yang GP. A review of biotransformation and pharmacology of ginsenoside compound K. Fitoterapia 2015;100:208-20. https://doi.org/10.1016/j.fitote.2014.11.019
  31. Bae HW, Kim JH, Kim S, Kim M, Lee N, Hong S, Seong GJ, Kim CY. Effect of Korean Red Ginseng supplementation on dry eye syndrome in glaucoma patients - a randomized, double-blind, placebo-controlled study. J Ginseng Res 2015;39:7-13. https://doi.org/10.1016/j.jgr.2014.07.002
  32. Shin BK, Park HY, Han J. Enzymatic biotransformation of red ginseng and the compositional change of ginsenosides. J Korean Soc Appl Bi 2010;53:553-8. https://doi.org/10.3839/jksabc.2010.085
  33. Trinh HT, Han SJ, Kim SW, Lee YC, Kim DH. Bifidus fermentation increases hypolipidemic and hypoglycemic effects of red ginseng. J Microbiol Biotechnol 2007;17:1127-33.
  34. Wang CZ, Li BH, Wen XD, Zhang ZY, Yu CH, Calway TD, He TC, Du W, Yuan CS. Paraptosis and NF-kappa B activation are associated with protopanaxadiolinduced cancer chemoprevention. Bmc Complem Altern M 2013;13.
  35. Akao T, Kanaoka M, Kobashi K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration-measurement of compound K by enzyme immunoassay. Biol Pharm Bull 1998;21:245-9. https://doi.org/10.1248/bpb.21.245
  36. Chen L, Zhou L, Huang J, Wang Y, Yang G, Tan Z, Wang Y, Zhou G, Liao J, Ouyang D. Single- and multiple-dose trials to determine the pharmacokinetics, safety, tolerability, and sex effect of oral ginsenoside compound K in healthy Chinese volunteers. Front Pharmacol 2017;8:965. https://doi.org/10.3389/fphar.2017.00965
  37. Chen L, Zhou L, Wang Y, Yang G, Huang J, Tan Z, Wang Y, Zhou G, Liao J, Ouyang D. Food and sex-related impacts on the pharmacokinetics of a singledose of ginsenoside compound K in healthy subjects. Front Pharmacol 2017;8:636. https://doi.org/10.3389/fphar.2017.00636
  38. Chen J, Li M, Chen L, Wang Y, Li S, Zhang Y, Zhang L, Song M, Liu C, Hua M, et al. Effects of processing method on the pharmacokinetics and tissue distribution of orally administered ginseng. J Ginseng Res 2018;42:27-34. https://doi.org/10.1016/j.jgr.2016.12.008
  39. Kim KA, Yoo HH, Gu W, Yu DH, Jin MJ, Choi HL, Yuan K, Guerin-Deremaux L, Kim DH. Effect of a soluble prebiotic fiber, NUTRIOSE, on the absorption of ginsenoside Rd in rats orally administered ginseng. J Ginseng Res 2014;38:203-7. https://doi.org/10.1016/j.jgr.2014.03.003
  40. Kim KA, Yoo HH, Gu W, Yu DH, Jin MJ, Choi HL, Yuan K, Guerin-Deremaux L, Kim DH. A prebiotic fiber increases the formation and subsequent absorption of compound K following oral administration of ginseng in rats. J Ginseng Res 2015;39:183-7. https://doi.org/10.1016/j.jgr.2014.11.002
  41. Mancuso C, Santangelo R. Panax ginseng and Panax quinquefolius: from pharmacology to toxicology. Food Chem Toxicol 2017;107:362-72. https://doi.org/10.1016/j.fct.2017.07.019
  42. Santangelo R, Silvestrini A, Mancuso C. Ginsenosides, catechins, quercetin and gut microbiota: current evidence of challenging interactions. Food Chem Toxicol 2019;123:42-9. https://doi.org/10.1016/j.fct.2018.10.042
  43. Zhang R, Huang XM, Yan HJ, Liu XY, Zhou Q, Luo ZY, Tan XN, Zhang BL. Highly selective production of compound K from ginsenoside Rd by hydrolyzing glucose at C-3 glycoside using beta-glucosidase of Bifidobacterium breve ATCC 15700. J Microbiol Biotechnol 2019;29:410-8. https://doi.org/10.4014/jmb.1808.08059
  44. Kong H, Wang M, Venema K, Maathuis A, van der Heijden R, van der Greef J, Xu G, Hankemeier T. Bioconversion of red ginseng saponins in the gastrointestinal tract in vitro model studied by high-performance liquid chromatography-high resolution Fourier transform ion cyclotron resonance mass spectrometry. J Chromatogr A 2009;1216:2195-203. https://doi.org/10.1016/j.chroma.2008.11.030

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