DOI QR코드

DOI QR Code

Pharmacokinetics of ginsenoside Rb1 and its metabolite compound K after oral administration of Korean Red Ginseng extract

  • Kim, Hyung-Ki (Department of Clinical Pharmacology, Soonchunhyang University College of Medicine)
  • Received : 2013.03.25
  • Accepted : 2013.08.01
  • Published : 2013.10.15

Abstract

Compound K is a major metabolite of ginsenoside Rb1, which has various pharmacological activities in vivo and in vitro. However, previous studies have focused on the pharmacokinetics of a single metabolite or the parent compound and have not described the pharmacokinetics of both compounds in humans. To investigate the pharmacokinetics of ginsenoside Rb1 and compound K, we performed an open-label, single-oral dose pharmacokinetic study using Korean Red Ginseng extract. We enrolled 10 healthy Korean male volunteers in this study. Serial blood samples were collected during 36 h after Korean Red Ginseng extract administration to determine plasma concentrations of ginsenoside Rb1 and compound K. The mean maximum plasma concentration of compound K was $8.35{\pm}3.19$ ng/mL, which was significantly higher than that of ginsenoside Rb1 ($3.94{\pm}1.97$ ng/mL). The half-life of compound K was 7 times shorter than that of ginsenoside Rb1. These results suggest that the pharmacokinetics, especially absorption, of compound K are not influenced by the pharmacokinetics of its parent compound, except the time to reach the maximum plasma concentration The delayed absorption of compound K support the evidence that the intestinal microflora play an important role in the transformation of ginsenoside Rb1 to compound K.

Keywords

References

  1. Christensen LP. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res 2009;55:1-99.
  2. Kang KS, Kim HY, Yamabe N, Nagai R, Yokozawa T. Protective effect of sun ginseng against diabetic renal damage. Biol Pharm Bull 2006;29:1678-1684. https://doi.org/10.1248/bpb.29.1678
  3. Yun TK. Panax ginseng: a non-organ-specific cancer preventive? Lancet Oncol 2001;2:49-55. https://doi.org/10.1016/S1470-2045(00)00196-0
  4. Qi LW, Wang CZ, Yuan CS. American ginseng: potential structure-function relationship in cancer chemoprevention. Biochem Pharmacol 2010;80:947-954. https://doi.org/10.1016/j.bcp.2010.06.023
  5. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-1693. https://doi.org/10.1016/S0006-2952(99)00212-9
  6. Gillis CN. Panax ginseng pharmacology: a nitric oxide link? Biochem Pharmacol 1997;54:1-8. https://doi.org/10.1016/S0006-2952(97)00193-7
  7. Paek IB, Moon Y, Kim J, Ji HY, Kim SA, Sohn DH, Kim JB, Lee HS. Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharm Drug Dispos 2006;27:39-45. https://doi.org/10.1002/bdd.481
  8. 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;25:743-747. https://doi.org/10.1248/bpb.25.743
  9. Hasegawa H, Sung JH, Benno Y. Role of human intestinal Prevotella oris in hydrolyzing ginseng saponins. Planta Med 1997;63:436-440. https://doi.org/10.1055/s-2006-957729
  10. Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31:1065-1071. https://doi.org/10.1124/dmd.31.8.1065
  11. Karikura M, Miyase T, Tanizawa H, Takino Y, Taniyama T, Hayashi T. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. V. The decomposition products of ginsenoside Rb2 in the large intestine of rats. Chem Pharm Bull (Tokyo) 1990;38:2859-2861. https://doi.org/10.1248/cpb.38.2859
  12. Hasegawa H, Uchiyama M. Antimetastatic efficacy of orally administered ginsenoside Rb1 in dependence on intestinal bacterial hydrolyzing potential and significance of treatment with an active bacterial metabolite. Planta Med 1998;64:696-700. https://doi.org/10.1055/s-2006-957560
  13. 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;50:1155-1160. https://doi.org/10.1111/j.2042-7158.1998.tb03327.x
  14. 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;21:245-249. https://doi.org/10.1248/bpb.21.245
  15. Wang CZ, Du GJ, Zhang Z, Wen XD, Calway T, Zhen Z, Musch MW, Bissonnette M, Chang EB, Yuan CS. Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer. Int J Oncol 2012;40:1970-1976.
  16. Wakabayashi C, Murakami K, Hasegawa H, Murata J, Saiki I. An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells. Biochem Biophys Res Commun 1998;246:725-730. https://doi.org/10.1006/bbrc.1998.8690
  17. Lee SJ, Sung JH, Lee SJ, Moon CK, Lee BH. Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin. Cancer Lett 1999;144:39-43. https://doi.org/10.1016/S0304-3835(99)00188-3
  18. Choo MK, Park EK, Han MJ, Kim DH. Antiallergic activity of ginseng and its ginsenosides. Planta Med 2003;69:518-522. https://doi.org/10.1055/s-2003-40653
  19. Baek NI, Kim DS, Lee YH, Park JD, Lee CB, Kim SI. Ginsenoside Rh4, a genuine dammarane glycoside from Korean red ginseng. Planta Med 1996;62:86-87. https://doi.org/10.1055/s-2006-957816
  20. Kim NR, Kim JH, Kim CY. Effect of Korean red ginseng supplementation on ocular blood flow in patients with glaucoma. J Ginseng Res 2010;34:237-245. https://doi.org/10.5142/jgr.2010.34.3.237
  21. Qi LW, Wang CZ, Du GJ, Zhang ZY, Calway T, Yuan CS. Metabolism of ginseng and its interactions with drugs. Curr Drug Metab 2011;12:818-822. https://doi.org/10.2174/138920011797470128
  22. Xie HT, Wang GJ, Sun JG, Tucker I, Zhao XC, Xie YY, Li H, Jiang XL, Wang R, Xu MJ et al. High performance liquid chromatographic-mass spectrometric determination of ginsenoside Rg3 and its metabolites in rat plasma using solid-phase extraction for pharmacokinetic studies. J Chromatogr B Analyt Technol Biomed Life Sci 2005;818:167-173. https://doi.org/10.1016/j.jchromb.2004.12.028
  23. Shibata S. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J Korean Med Sci 2001;16 Suppl:S28-S37. https://doi.org/10.3346/jkms.2001.16.S.S28
  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;139:664-667. https://doi.org/10.1016/j.jep.2011.11.052
  25. 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;37:135-141. https://doi.org/10.5142/jgr.2013.37.135
  26. 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;122:143-148. https://doi.org/10.1016/j.jep.2008.12.012

Cited by

  1. Membrane Interactions of Phytochemicals as Their Molecular Mechanism Applicable to the Discovery of Drug Leads from Plants vol.20, pp.10, 2015, https://doi.org/10.3390/molecules201018923
  2. Compound K, a Metabolite of Ginsenosides, Attenuates Collagen-induced Arthritis in Mice vol.22, pp.3, 2015, https://doi.org/10.4078/jrd.2015.22.3.154
  3. Recent advances in ginseng as cancer therapeutics: a functional and mechanistic overview vol.32, pp.2, 2015, https://doi.org/10.1039/C4NP00080C
  4. in rats: in vitro and in vivo insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis vol.7, pp.15, 2015, https://doi.org/10.1039/C5AY01098E
  5. Profiling and identification of the metabolites of ginsenoside Ro in rat faeces and urine after oral administration vol.242, pp.2, 2016, https://doi.org/10.1007/s00217-015-2531-x
  6. Metabolic profile and pharmacokinetics of polyphyllin I, an anticancer candidate, in rats by UPLC-QTOF-MS/MS and LC-TQ-MS/MS vol.31, pp.3, 2017, https://doi.org/10.1002/bmc.3817
  7. Compound K derived from ginseng: neuroprotection and cognitive improvement vol.7, pp.11, 2016, https://doi.org/10.1039/C6FO01077F
  8. Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRα Activator vol.22, pp.7, 2017, https://doi.org/10.3390/molecules22071232
  9. Ultra-fast liquid chromatography with tandem mass spectrometry determination of eight bioactive components of Kai-Xin-San in rat plasma and its application to a comparative pharmacokinetic study in normal and Alzheimer's disease rats vol.40, pp.10, 2017, https://doi.org/10.1002/jssc.201601343
  10. Food and Sex-Related Impacts on the Pharmacokinetics of a Single-Dose of Ginsenoside Compound K in Healthy Subjects vol.8, pp.1663-9812, 2017, https://doi.org/10.3389/fphar.2017.00636
  11. Inhibition of Cholesterol Synthesis in HepG2 Cells by GINST-Decreasing HMG-CoA Reductase Expression Via AMP-Activated Protein Kinase vol.82, pp.11, 2017, https://doi.org/10.1111/1750-3841.13828
  12. Simultaneous determination of baicalin, baicalein, wogonoside, wogonin, scutellarin, berberine, coptisine, ginsenoside Rb1 and ginsenoside Re of Banxia xiexin decoction in rat plasma by LC-MS/MS and its application to a pharmacokinetic study pp.02693879, 2017, https://doi.org/10.1002/bmc.4083
  13. The Effects of a Korean Ginseng, GINST15, on Hypo-Pituitary-Adrenal and Oxidative Activity Induced by Intense Work Stress pp.1557-7600, 2017, https://doi.org/10.1089/jmf.2017.0071
  14. Cancer chemoprevention and therapy using chinese herbal medicine vol.20, pp.1, 2018, https://doi.org/10.1186/s12575-017-0066-1
  15. Effects of Red Ginseng Extract on the Pharmacokinetics and Elimination of Methotrexate via Mrp2 Regulation vol.23, pp.11, 2018, https://doi.org/10.3390/molecules23112948
  16. Pharmacokinetic and Metabolism Studies of 12-Riboside-Pseudoginsengenin DQ by UPLC-MS/MS and UPLC-QTOF-MSE vol.23, pp.10, 2018, https://doi.org/10.3390/molecules23102499
  17. An Insight into Ginsenoside Metabolite Compound K as a Potential Tool for Skin Disorder vol.2018, pp.1741-4288, 2018, https://doi.org/10.1155/2018/8075870
  18. Single- and Multiple-Dose Trials to Determine the Pharmacokinetics, Safety, Tolerability, and Sex Effect of Oral Ginsenoside Compound K in Healthy Chinese Volunteers vol.8, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2017.00965
  19. Enhanced Absorption Study of Ginsenoside Compound K (20- O - β -(D-Glucopyranosyl)-20(S)-protopanaxadiol) after Oral Administration of Fermented Red Ginseng Extract (HYFRG ™ ) in Healthy Korean vol.2016, pp.None, 2013, https://doi.org/10.1155/2016/3908142
  20. Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation vol.7, pp.8, 2013, https://doi.org/10.1038/cddis.2016.234
  21. Ginsenoside-Rb1 targets chemotherapy-resistant ovarian cancer stem cells via simultaneous inhibition of Wnt/β-catenin signaling and epithelial-to-mesenchymal transition vol.8, pp.16, 2013, https://doi.org/10.18632/oncotarget.13071
  22. Ginsenosides Act As Positive Modulators of P2X4 Receptors vol.95, pp.2, 2013, https://doi.org/10.1124/mol.118.113696
  23. LC-MS/MS determination of ginsenoside compound K and its metabolite 20 (S)-protopanaxadiol in human plasma and urine: applications in a clinical study vol.11, pp.5, 2013, https://doi.org/10.4155/bio-2018-0185
  24. Interactions of ginseng with therapeutic drugs vol.42, pp.10, 2013, https://doi.org/10.1007/s12272-019-01184-3
  25. Interactions Between Gut Microbiota, Host, and Herbal Medicines: A Review of New Insights Into the Pathogenesis and Treatment of Type 2 Diabetes vol.10, pp.None, 2013, https://doi.org/10.3389/fcimb.2020.00360
  26. Pharmacokinetics and Intestinal Metabolism of Compound K in Rats and Mice vol.12, pp.2, 2020, https://doi.org/10.3390/pharmaceutics12020129
  27. Chinese Herbal Medicine Interventions in Neurological Disorder Therapeutics by Regulating Glutamate Signaling vol.18, pp.4, 2013, https://doi.org/10.2174/1570159x17666191101125530
  28. The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury vol.20, pp.16, 2020, https://doi.org/10.2174/1389557520666200619115444
  29. Chemical components of ginseng, their biotransformation products and their potential as treatment of hypertension vol.476, pp.1, 2013, https://doi.org/10.1007/s11010-020-03910-8
  30. A Synergistic Anti-Diabetic Effect by Ginsenosides Rb1 and Rg3 through Adipogenic and Insulin Signaling Pathways in 3T3-L1 Cells vol.11, pp.4, 2021, https://doi.org/10.3390/app11041725
  31. Effect of Lactic Acid Bacteria on the Pharmacokinetics and Metabolism of Ginsenosides in Mice vol.13, pp.9, 2013, https://doi.org/10.3390/pharmaceutics13091496
  32. Network Pharmacology of Red Ginseng (Part I): Effects of Ginsenoside Rg5 at Physiological and Sub-Physiological Concentrations vol.14, pp.10, 2013, https://doi.org/10.3390/ph14100999
  33. Network Pharmacology of Ginseng (Part II): The Differential Effects of Red Ginseng and Ginsenoside Rg5 in Cancer and Heart Diseases as Determined by Transcriptomics vol.14, pp.10, 2013, https://doi.org/10.3390/ph14101010
  34. Determination of ginsenoside Rh3 in rat plasma by LC–MS/MS and its application to a pharmacokinetic study vol.36, pp.2, 2013, https://doi.org/10.1002/bmc.5268