Skip to main content
SpringerLink
Log in

Pharmacokinetics of Single Ascending Doses and Multiple Doses of 20(S)-Ginsenoside Rg3 in Chinese Healthy Volunteers

  • Short Communication
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

20(S)-Ginsenoside Rg3 could significantly inhibit tumor growth and metastasis in animals and in in vitro tumor cell invasion. This first-in-human pharmacokinetic study investigated the pharmacokinetics of 20(S)-ginsenoside Rg3 (hip intramuscular injection) in healthy Chinese volunteers.

Methods

Study 1 investigated single, ascending intramuscular doses of 10–60 mg of 20(S)-ginsenoside Rg3 in 24 healthy adults; study 2 evaluated multiple intramuscular doses of 30 mg of 20(S)-ginsenoside Rg3 administered for 15 days in 9 healthy adults.

Results

In both studies, 20(S)-ginsenoside Rg3 was rapidly absorbed, with a time to reach maximum plasma concentration (T max) of 4 h. After single-dose administration, elimination half-life t ½ was 32.0 ± 26.7, 51.7 ± 15.4 and 53.9 ± 25.7 h; maximum plasma concentration (C max) was 135.4 ± 35.3, 162.1 ± 47.2 and 399.8 ± 217.0 ng/mL; area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC0–∞) was 3474.1 ± 1312.3, 8156.5 ± 1782.7 and 25,666.8 ± 9401.1 ng·h/mL; clearance CL/F was 3.2 ± 0.9, 3.8 ± 0.7 and 2.7 ± 1.3 L/h; urine excretion percentage during 72 h was 0.5 ± 0.1, 0.4 ± 0.1 and 0.4 ± 0.2 % after 10, 30 and 60 mg 20(S)-ginsenoside Rg3, respectively. After multiple-dose administration, C max was 457.0 ± 165.7 and 770.2 ± 275.4 ng/mL; AUC0–48h was 10,530.0 ± 4073.9 and 16,871.3 ± 6939.3 ng·h/mL after the first and the last 20(S)-ginsenoside Rg3 doses, respectively; fluctuation percentage was 183.0 ± 46.3 %. Accumulation ratio was 1.7 ± 0.6 at steady state.

Conclusions

20(S)-ginsenoside Rg3 was generally well tolerated. In these studies, 20(S)-ginsenoside Rg3 exhibited a pharmacokinetic profile suitable for once-every-2-days dosing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Chang L, Huo B, Lv Y, Wang Y, Liu W. Ginsenoside Rg3 enhances the inhibitory effects of chemotherapy on esophageal squamous cell carcinoma in mice. Mol Clin Oncol. 2014;2:1043–6.

    PubMed  PubMed Central  Google Scholar 

  2. Lu P, Su W, Miao ZH, Niu HR, Liu J, Hua QL. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin J Integr Med. 2008;14:33–6.

    Article  CAS  PubMed  Google Scholar 

  3. Huang JY, Sun Y, Fan QX, Zhang YQ. Efficacy of Shenyi capsule combined with gemcitabine plus cisplatin in treatment of advanced esophageal cancer: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao. 2009;7:1047–51 [In Chinese].

    Article  PubMed  Google Scholar 

  4. Li J, Liu T, Zhao L, Chen W, Hou H, Ye Z, Li X. Ginsenoside 20(S)-Rg3 inhibits the Warburg effect through STAT3 pathways in ovarian cancer cells. Int J Oncol. 2015;46:775–81.

    CAS  PubMed  Google Scholar 

  5. Guo JQ, Zheng QH, Chen H, Chen L, Xu JB, Chen MY, Lu D, Wang ZH, Tong HF, Lin S. Ginsenoside Rg3 inhibition of vasculogenic mimicry in pancreatic cancer through downregulation of VE-cadherin/EphA2/MMP9/MMP2 expression. Int J Oncol. 2014;45:1065–72.

    PubMed  Google Scholar 

  6. Mochizuki M, Yoo YC, Matsuzawa K, Sato K, Saiki I, Tono-oka S, Samukawa K, Azuma I. Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20(R)- and 20(S)-ginsenoside-Rg3, of red ginseng. Biol Pharm Bull. 1995;18:1197–202.

    Article  CAS  PubMed  Google Scholar 

  7. Zhou B, Wang J, Yan Z. Ginsenoside Rg3 attenuates hepatoma VEGF overexpression after hepatic artery embolization in an orthotopic transplantation hepatocellular carcinoma rat model. Oncol Targets Ther. 2014;7:1945–54.

    Article  CAS  Google Scholar 

  8. Lee SY, Kim GT, Roh SH, Song JS, Kim HJ, Hong SS, Kwon SW, Park JH. Proteomic analysis of the anti-cancer effect of 20S-ginsenoside Rg3 in human colon cancer cell lines. Biosci Biotechnol Biochem. 2009;73:811–6.

    Article  CAS  PubMed  Google Scholar 

  9. Yang R, Chen D, Li M, Miao F, Liu P, Tang Q. 20(S)-ginsenoside Rg3-loaded magnetic human serum albumin nanospheres applied to HeLa cervical cancer cells in vitro. Biomed Mater Eng. 2014;24:1991–8.

    CAS  PubMed  Google Scholar 

  10. Qiu XM, Bai X, Jiang HF, He P, Wang JH. 20-(s)-ginsenoside Rg3 induces apoptotic cell death in human leukemic U937 and HL-60 cells through PI3 K/Akt pathways. Anticancer Drugs. 2014;25:1072–80.

    Article  CAS  PubMed  Google Scholar 

  11. Kim DG, Jung KH, Lee DG, Yoon JH, Choi KS, Kwon SW, Shen HM, Morgan MJ, Hong SS, Kim YS. 20(S)-ginsenoside Rg3 is a novel inhibitor of autophagy and sensitizes hepatocellular carcinoma to doxorubicin. Oncotarget. 2014;5:4438–51.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim BM, Kim DH, Park JH, Na HK, Surh YJ. Ginsenoside Rg3 Induces Apoptosis of Human Breast Cancer (MDA-MB-231) Cells. J Cancer Prev. 2013;18:177–85.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lim CJ, Choi WY, Jung HJ. Stereoselective skin anti-photoaging properties of ginsenoside Rg3 in UV-B-irradiated keratinocytes. Biol Pharm Bull. 2014;37:1583–90.

    Article  CAS  PubMed  Google Scholar 

  14. Park EH, Kim YJ, Yamabe N, Park SH, Kim HK, Jang HJ, Kim JH, Cheon GJ, Ham J, Kang KS. Stereospecific anticancer effects of ginsenoside Rg3 epimers isolated from heat-processed American ginseng on human gastric cancer cell. J Ginseng Res. 2014;38:22–7.

    Article  CAS  PubMed  Google Scholar 

  15. Kwok HH, Guo GL, Lau JK, Cheng YK, Wang JR, Jiang ZH, Keung MH, Mak NK, Yue PY, Wong RN. Stereoisomers ginsenosides-20(S)-Rg3 and -20(R)-Rg3 differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma. Biochem Pharmacol. 2012;83:893–902.

    Article  CAS  PubMed  Google Scholar 

  16. Pang H, Wang HL, Fu L, Su CY. Pharmacokinetics of 20(R)-ginsenoside Rg3 in human volunteers. Yao Xue Xue Bao. 2001;36:170–3 [In Chinese].

    CAS  PubMed  Google Scholar 

  17. Coon JT, Ernst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Saf. 2002;25:323–44.

    Article  CAS  PubMed  Google Scholar 

  18. Park SH, Oh MR, Choi EK, Kim MG, Ha KC, Lee SK, Kim YG, Park BH, Kim DS, Chae SW. An 8-wk, randomized, double-blind, placebo-controlled clinical trial for the antidiabetic effects of hydrolyzed ginseng extract. J Ginseng Res. 2014;38:239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Choi J, Kim TH, Choi TY, Lee MS. Ginseng for health care: a systematic review of randomized controlled trials in Korean literature. PLoS One. 2013;8:e59978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhao Q, Zheng X, Jiang J, Zhou H, Hu P. Determination of ginsenoside Rg3 in human plasma and urine by high performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878:2266–73.

    Article  CAS  PubMed  Google Scholar 

  21. Lai L, Hao H, Liu Y, Zheng C, Wang Q, Wang G, Chen X. Characterization of pharmacokinetic profiles and metabolic pathways of 20(S)-ginsenoside Rh1 in vivo and in vitro. Planta Med. 2009;75:797–802.

    Article  CAS  PubMed  Google Scholar 

  22. Liu H, Yang J, Du F, Gao X, Ma X, Huang Y, Xu F, Niu W, Wang F, Mao Y, Sun Y, Lu T, Liu C, Zhang B, Li C. Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. Drug Metab Dispos. 2009;37:2290–8.

    Article  CAS  PubMed  Google Scholar 

  23. Sun C, Li Y, Wu Q, Luo H, Sun Y, Song J, Lui EM, Chen S. De novo sequencing and analysis of the American ginseng root transcriptome using a GS FLX Titanium platform to discover putative genes involved in ginsenoside biosynthesis. BMC Genomics. 2010;11:262.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jiang R, Dong J, Li X, Du F, Jia W, Xu F, Wang F, Yang J, Niu W, Li C. Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside-perpetrated herb-drug interactions on OATP1B3. Br J Pharmacol. 2015;172(4):1059–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liang Y, Zhou Y, Zhang J, Rao T, Zhou L, Xing R, Wang Q, Fu H, Hao K, Xie L, Wang G. Pharmacokinetic compatibility of ginsenosides and Schisandra Lignans in Shengmai-san: from the perspective of p-glycoprotein. PLoS One. 2014;9(6):e98717.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Li XX, Zhang CC, Xiong YK. Review of studies on the pharmacokinetics of Ginsenoside. Chin Pharm J. 2012;47:1101–4 (in Chinese).

    CAS  Google Scholar 

  27. Qian T, Cai Z, Wong RN, Jiang ZH. Liquid chromatography/mass spectrometric analysis of rat samples for in vivo metabolism and pharmacokinetic studies of ginsenoside Rh2. Rapid Commun Mass Spectrom. 2005;19:3549–54.

    Article  CAS  PubMed  Google Scholar 

  28. Qian T, Cai Z, Wong RN, Mak NK, Jiang ZH. In vivo rat metabolism and pharmacokinetic studies of ginsenoside Rg3. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;816:223–32.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang J, Zhou F, Niu F, Lu M, Wu X, Sun J, Wang G. Stereoselective regulations of P-glycoprotein by ginsenoside Rh2 epimers and the potential mechanisms from the view of pharmacokinetics. PLoS One. 2012;7:e35768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jeong SM, Lee JH, Kim JH, Lee BH, Yoon IS, Lee JH, Kim DH, Rhim H, Kim Y, Nah SY. Stereospecificity of ginsenoside Rg3 action on ion channels. Mol Cells. 2004;18:383–9.

    CAS  PubMed  Google Scholar 

  32. Kim JH, Lee JH, Jeong SM, Lee BH, Yoon IS, Lee JH, Choi SH, Kim DH, Park TK, Kim BK, et al. Stereospecific effects of ginsenoside Rg3 epimers on swine coronary artery contractions. Biol Pharm Bull. 2006;29:365–70.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang W, Bai X, Wang Y, Zhao B, Zhao Y, Hou W, Jin Y, Zhao D. SERS study of different configurations of pharmaceutical and natural product molecules ginsenoside Rg3 under the interaction with human serum albumin on simple self-assembled substrate. Spectrochim Acta A Mol Biomol Spectrosc. 2014;117:210–5.

    Article  CAS  PubMed  Google Scholar 

  34. Gu Y, Wang GJ, Wu XL, Zheng YT, Zhang JW, Ai H, Sun JG, Jia YW. Intestinal absorption mechanisms of ginsenoside Rh2: stereoselectivity and involvement of ABC transporters. Xenobiotica. 2010;40:602–12.

    Article  CAS  PubMed  Google Scholar 

  35. Bae SH, Zheng YF, Yoo YH, Kim JY, Kim SO, Jang MJ, Seo JH, Bae SK. Stereoselective determination of ginsenosides Rg3 and Rh2 epimers in rat plasma by LC-MS/MS: application to a pharmacokinetic study. J Sep Sci. 2013;36:1904–12.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank staff in the study team and all study subjects. This study was sponsored by Beijing Xinliheng Pharmaceutical Technology Development Co., Ltd.

Author information

Authors and Affiliations

  1. Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 41 Damuchang, Xicheng District, 100032, Beijing, China

    Qian Zhao, Ji Jiang & Pei Hu

  2. Institute of Frontier Medical Science of Jilin University, Changchun, 130021, China

    Pingya Li

Authors
  1. Qian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pingya Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ji Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pei Hu.

Ethics declarations

Funding

The work was supported by a grant from the National Program on Key Research Project of New Drug Innovation (No. 2008ZX09312 and No. 2012ZX09303006-002).

Conflict of interest

Qian Zhao, Pingya Li, Ji Jiang and Pei Hu declare no conflict of interest.

Ethical approval

Study protocols and the informed consent forms were approved by the independent ethics committee of Peking Union Medical College Hospital (PUMCH).

Informed consent

Subjects provided written informed consent before study participation.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, Q., Li, P., Jiang, J. et al. Pharmacokinetics of Single Ascending Doses and Multiple Doses of 20(S)-Ginsenoside Rg3 in Chinese Healthy Volunteers. Eur J Drug Metab Pharmacokinet 41, 845–853 (2016). https://doi.org/10.1007/s13318-015-0304-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-015-0304-3

Keywords

Search

Navigation