Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Metabolism and drug interactions of Korean ginseng based on the pharmacokinetic properties of ginsenosides: Current status and future perspectives

  • Received : 2024.01.17
  • Accepted : 2024.02.24
  • Published : 2024.05.01
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Abstract

Orally administered ginsenosides, the major active components of ginseng, have been shown to be biotransformed into a number of metabolites by gastric juice, digestive and bacterial enzymes in the gastrointestinal tract and also in the liver. Attention is brought to pharmacokinetic studies of ginseng that need further clarification to better understand the safety and possible active mechanism for clinical application. Experimental results demonstrated that ginsenoside metabolites play an important role in the pharmacokinetic properties such as drug metabolizing enzymes and drug transporters, thereby can be applied as a metabolic modulator. Very few are known on the possibility of the consistency of detected ginsenosides with real active metabolites if taken the recommended dose of ginseng, but they have been found to act on the pharmacokinetic key factors in any clinical trial, affecting oral bioavailability. Since ginseng is increasingly being taken in a manner more often associated with prescription medicines, ginseng and drug interactions have been also reviewed. Considering the extensive oral administration of ginseng, the aim of this review is to provide a comprehensive overview and perspectives of recent studies on the pharmacokinetic properties of ginsenosides such as deglycosylation, absorption, metabolizing enzymes and transporters, together with ginsenoside and drug interactions.

Keywords

Acknowledgement

The author is deeply indebted to the late Dr. Ki Yeul Nam for his dedicated support.

References

  1. Kobashi K. Glycosides are natural prodrugs: evidence using germfree and gnotobiotic rats associated with a human intestinal bacterium. J Tradit Med 1998;15:1-13. 
  2. Park JD. Recent studies on the chemical constituents of Korean ginseng(Panax ginseng C. A. Meyer). J Ginseng Res 1996;20:389-415. 
  3. Yang L, Liu Y, Liu CX. Metabolism and pharmacokinetics of ginsenosides. Asian Journal of Pharmacodynamics and Pharmacokinetics 2006;6:103-20. 
  4. Cho HJ, Yoon IS. Pharmacokinetic interactions of herbs with cytochrome p450 and p-glycoprotein. Evid Based Complement Alternat Med 2015;2015:1-10.  https://doi.org/10.1155/2015/736431
  5. Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lance 2007;370:185-91. 2007.  https://doi.org/10.1016/S0140-6736(07)61092-7
  6. Nam KY, Yang BW, Shin WS, Park JD. A systematic review on potential drug interactions of Korean ginseng based upon cytochrome P450 and P-glycoprotein. Korean J Pharmacogn 2018;49:85-102. 
  7. Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. VI. The decomposition products of ginsenoside Rb2 in the stomach of rats. Chem Pharm Bull 1991;39:400-4.  https://doi.org/10.1248/cpb.39.400
  8. Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. VII. Comparison of the decomposition modes of ginsenosides Rb1 and Rb2 in the digestive gtract of rats. Chem Pharm Bull 1991;39:2357-61.  https://doi.org/10.1248/cpb.39.2357
  9. Bae EA, Han MJ, Kim EJ, Kim DH. Transformation of ginseng saponins to ginsenoside Rh2 by acids and human intestinal bacteria and biological activities of their transformants. Arch Pharm Res (Seoul) 2004;27:61-7.  https://doi.org/10.1007/BF02980048
  10. Takino Y. Studies on the pharmacodynamics of ginsenoside Rg1, Rb1 and Rb2 in rats. Yakugaku Zasshi 1994;114:550-64.  https://doi.org/10.1248/yakushi1947.114.8_550
  11. Huang J, Gong MJ, Bai JQ, Su H, Gong L, Huang ZH, Qiu XH, Xu W, Zhang J. Differential metabolic profiles of ginsenosides in artificial gastric juice using ultra-high-pressure liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry. Biomed Chromatogr 2022;36:e5493.  https://doi.org/10.1002/bmc.5493
  12. Nicholson JK, Holmes E, Wilson ID. Gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Microbial 2005;3:431-8.  https://doi.org/10.1038/nrmicro1152
  13. Hasegawa H, Sung JH, Benno Y. Role of human intestinal Prevotella oris in hydrolyzing ginseng saponin. Planta Med 1997;63:436-40.  https://doi.org/10.1055/s-2006-957729
  14. Bae EA, Park SY, Kim DH. Constitutive β-glucosidases hydrolysing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull 2000;23:1481-5.  https://doi.org/10.1248/bpb.23.1481
  15. Lee DS, Kim YS, Ko CN, Cho KH, Bae HS, Lee KS, Kim JJ, Park EK, Kim DH. Fecal metabolic activities of herbal components to bioactive compounds. Arch Pharm Res (Seoul) 2022;25:165-9.  https://doi.org/10.1007/BF02976558
  16. Karikura M, Miyase T, Tanizawa H, Takino Y, Taniyama T, Hayashi T. Studies on absorption, distribution, excretion and metabolism of ginseng saponin. V. The decomposition products of ginsenoside Rb2 in the large intestine of rats. Chem Pharm Bull 1990;38:2859-61.  https://doi.org/10.1248/cpb.38.2859
  17. Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponin. VII. Comparison of rhe decomposition modes of ginsenosides Rb1 and Rb2 in the digestive tract of rats. Chem Pharm Bull 1991;39:2357-61.  https://doi.org/10.1248/cpb.39.2357
  18. Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH. Metabolism of ginsenoside Rc by human intestinal bacteria and its related antiallergic activity. Biol Pharm Bull 2002;25:743-7.  https://doi.org/10.1248/bpb.25.743
  19. Wang Y, Liu TH, Wang W, Wang BX. Research on the transformation of ginsenoside Rg1 by intestinal flora. Zhongguo Zhongyao Zazhi 2001;26:188-90. 
  20. 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
  21. Hasegawa H. Proof of the mysterious efficacy of ginseng : basic and clinical trials : metabolic activation of ginsenoside : deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci 2004;95:153-7.  https://doi.org/10.1254/jphs.FMJ04001X4
  22. Jeon JH, Park JH, Jeon SY, Pang M, Choi MK, Song IS. Concomitent administration of red ginseng extract with lactic acid bacteria increasess the plasma concentration of deglycosylated ginsenosides in healthy human subjects. Biomolecules 2022;12:1896. https://doi.org/10.3390/biom12121896. 
  23. 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
  24. Kanaoka M, Kato H, Shimada F, Yano S. Studies on the enzyme immuno-assay of bioactive constituents in oriental medicinal drugs VII : enzyme immuno-assay of ginsenoside Rb1 from Panax ginseng. Chem Pharm Bull 1992;40:314-7.  https://doi.org/10.1248/cpb.40.314
  25. Akao T, Kida H, Kanaok M, Hattori M, Kobashi M. 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
  26. 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
  27. 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
  28. Qian T, Cai Z, Wong RN, Mak NK, Jiang ZH. In vivo rat metabolism and pharmacokinetic studies of ginsenoside Rg3. J Chromatogr, B: Anal Technol Biomed Life Sci 2005;816:223-32.  https://doi.org/10.1016/j.jchromb.2004.11.036
  29. Pang H, Wang HL, Fu L, Sui CY. Pharmacokinetic studies of 20(R)-ginsenoside Rg3 in human volunteers. Yao Xue Xue Bao 2001;36:170-3. 
  30. Kim EO, Cha KH, Lee EH, Kim SM, Choi SW, Pan CH, Um BH. Bioavailability of ginsenosides from white and red ginsengs in the simulated digestion model. J Agric Food Chem 2014;62:10055-63.  https://doi.org/10.1021/jf500477n
  31. Pan W, Xue B, Yang C, Miao L, Zhou L, Chen Q, Cai Q, Liu Y, Liu D, He H, Zhang Y, Yin T, Tang X. Biopharmaceutical characters and bioavailability improving strategies of ginsenosides. Fitoterapia 2018;129:272-82.  https://doi.org/10.1016/j.fitote.2018.06.001
  32. Wang M, Li H, Liu W, Cao H, Hu X, Gao X, Xu F, Li Z, Hua H, Li D. Dammaran-type leads panaxadiol and protopanaxadiol for drug discovery: biological activity and structural modification. Eur J Med Chem 2020;189:112087. 
  33. Paek IB, Moon Y, Kim J, Ji HY, Kin SA, Sohn DH, Kim JB, Lee HS. Pharmacokinetics of a ginseng saponion metabolite compound K in rats. Biopharm Drug Dispos 2006;27:39-45.  https://doi.org/10.1002/bdd.481
  34. Hasegawa H, Sung JH, Matsumiya S, Uchiyama M. Main ginseng saponin metabolites formed by intestinal bacteria. Planta Med 1996;62:453-7.  https://doi.org/10.1055/s-2006-957938
  35. Wakabayashi G, Hasegawa H, Murata J, Saiki I. In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal metabolites after oral administration. Oncol Res 1997;9:411-7. 
  36. Tawab MA, Bahr U, Karas M, Wurglics M, Schbert-Zsilavecz M. Degradation of gisenosides in human after oral administration. Drug Metab Dispos 2003;31:1065-71.  https://doi.org/10.1124/dmd.31.8.1065
  37. Ryu JS, Lee HJ, Bae SH, Kim SY, Park Y, Suh HJ, Jeong YH. The bioavailability of red ginseng extract fermented by Phellinus Linteus. J Ginseng Res 2013;37:108-16.  https://doi.org/10.5142/jgr.2013.37.108
  38. 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
  39. Fukami H, Ueda T, Matsuoka N. Pharmacokinetic study of compound K in Japanese subjects after ingestion of Panax ginseng fermented by Lactobacillus paracasei A221 reveals significant increase of absorption into blood. J Med Food 2018. https://doi.org/10.1089/jmf.2018.4271. 
  40. Chen Z, Zhang Z, Liu J, Qi H, Li J, Chen J, Huang Q, Liu Q, Mi Q, Li X. Gut microbiota: therapeutic targets of ginseng against multiple disorders and ginsenoside transformation. Front Cell Infect Microbiol 2022;12:853981. 
  41. Hasegawa H, Lee KS, Nagoka T, Tezuka Y, Uchiyama M, Kadota S, Saiki I. Pharmacokinetics of ginsenoside deglycosylation by intestinal bacteria and its transformation to biologically active fatty acid esters. Biol Pharm Bull 2000;23:298-304.  https://doi.org/10.1248/bpb.23.298
  42. Hasegawa H, Suzuki R, Nagoka T, Tezuka Y, Kadota S, Saiki I. Prevention of growth and metastasis of murine melanoma through enhanced natural killer cytotoxicity by fatty acid conjugate of protopnaxatriol. Biol Pharm Bull 2002;25:861-6.  https://doi.org/10.1248/bpb.25.861
  43. Hao H, Lai L, Zheng C, Wang Q, Yu G, Zhou X, Wu L, Gong P, Wang G. Microsomal cytochrome P450-mediated metabolism of protopanaxadiol ginsenosides: metabolic profile, reaction phenotyping, and structure-metabolism relationship. Drug Metabol Dispos 2010;38:1731-9.  https://doi.org/10.1124/dmd.110.033845
  44. Ma LY, Zhou QL, Yang XB, Wang HP, Yang XW. Metabolism of 20(S)-ginsenoside Rg2 by rat liver microsomes: bioactivation to SIRT1-activating metabolites. Molecules 2016;21:757. https://doi.org/10.3390/molecules21060757. 
  45. Tanizawa H, Karikuma M, Miyase T, Takino Y. Studies on the metabolism and decomposition and distribution of ginsenoside Rb2 in rats. Proc 6th Int Ginseng Symp 1993:187-94. 
  46. Kim SW, Han BC, So SH, Han CK, In G, Park CK, Hyun SH. Biodistribution and pharmacokinetic evaluation of Koran red ginseng components using radioisotopes in a rat model. J Ginseng Res 2023;47:74-80.  https://doi.org/10.1016/j.jgr.2022.05.001
  47. Ban MS, Kim Y, Lee S, Han BY, Yu KS, Jang IJ, Chung HK, Lee SH. Pharmacokinetics of ginsenoside compound K from a compound K fermentation product, CK-30, and from red ginseng extract in healthy Korean subjects. Clinical Pharmacology in Drug Development 2021;00:1-7.  https://doi.org/10.1002/cpdd.949
  48. Sharma A, Lee HJ. Ginsenoside compound K: insights into recent studies on pharmacokinetics and health-promoting activities. Biomolecules 2020;10:1028. https://doi.org/10.3390/biom10071028. 
  49. Chen J, Li M, Chen L, Wang Y, Li S, Zhang Y, Zhang L, Song M, Liu C, Hua M, Sun Y. 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
  50. Kim JK, Choi MS, Jeung W, Ra J, Yoo HH, Kim DH. Effects of gut microbiota on the pharmacokinetics of protopanxadiol ginsenosides Rd, Rg3, F2 and compound K in healthy volunteers treated orally with red ginseng. J Ginseng Res 2020;44:611-8.  https://doi.org/10.1016/j.jgr.2019.05.012
  51. Won HJ, Kim HI, Park T, Kim H, Jo K, Jeon H, Ha SJ, Hyun JM, Jeong A, Kim JS, Park YJ, Eo YH, Lee J. Non-clinical pharmacokinetic behavior of ginsenosides. J Ginseng Res 2019;43:354-60.  https://doi.org/10.1016/j.jgr.2018.06.001
  52. Miao L, Yang Y, Li Z, Fang Z, Zhang Y, Han C. Ginsenoside Rb2: a review of pharmacokinetics and pharmacological effects. J Ginseng Res 2022;46:206-13.  https://doi.org/10.1016/j.jgr.2021.11.007
  53. Kim HJ, Oh TK, Kim YH, Lee J, Moon JM, Park YS, Sung CM. Pharmacokinetics of ginsenoside Rb1, Rg3, Rk1, Rg5, F2, and compound K from red ginseng extract in healthy Korean volunteers. Evid Based Complement Alternat Med 2022;Jan;24:8427519. https://doi.org/10.1155/2022/8427519.2022. 
  54. Guengerich FP. Cytochrome P-450 3A4 : regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999;39:1-17.  https://doi.org/10.1146/annurev.pharmtox.39.1.1
  55. Liu Y, Zhang JW, Li W, Ma H, Sun J, Deng MC, Yang L. Ginsenoside metabolites, rather than naturally occurring ginsenosides, lead to inhibition of human cytochrome P450 enzymes. Toxicol Sci 2006;91:356-64.  https://doi.org/10.1093/toxsci/kfj164
  56. Liu Y, Li W, Li P, Deng MC, Yang SL, Yang L. The inhibitory effect of intestinal bacterial metabolite of ginsenosides on CYP3A activity. Biol Pharm Bull 2004;27:1555-60.  https://doi.org/10.1248/bpb.27.1555
  57. Xiao J, Chen D, Lin XX, Peng SF, Xiao MF, Huang WH, Wang YC, Peng JB, Zhang W, Ouyang DS, Chen Y. Screening of drug metabolizing enzymes for the ginsenoside compound K in vitro : an efficient anticancer substance originating from Panax ginseng. PLoS One 2016;11:e0147183. 
  58. Chiu N, Tomlinson Guns ES, Adomat H, Jia W, Deb S. Idntification of human cytochrome P450 enzymes involved in the hepatic and intestinal biotransformation of 20(S)-protopanaxadiol. Biopharm Drug Dispos 2014;35:104-18.  https://doi.org/10.1002/bdd.1873
  59. Deb S, Chin M, Adomat H, Guns ES. Ginsenoside-mediated blockade of 1α, 25-dihydroxyvitamin D3 inactivation in human liver and intestine in vitro. J Steroid Biochem Mol Biol 2014;141:94-103.  https://doi.org/10.1016/j.jsbmb.2014.01.007
  60. Hao M, Zhao Y, Chen P, Huang H, Liu H, Jiang H, Zhang R, Wang H. Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes. PLoS One 2008;3:e2697. 
  61. Hao M, Ba Q, Yin J, Li J, Zhao Y, Wang H. Deglycosylated ginsenosides are more potent inducers of CYP1A1, CYP1A2 and CYP3A4 expression in HepG2 cells than glycosylated ginsenosides. Drug Metabol Pharmacokinet 2011;26:201-5.  https://doi.org/10.2133/dmpk.DMPK-10-NT-056
  62. Lee SG, Cho KH, Nguyen TTL, Vo DK, Chae YJ, Maeng HJ. Inhibitory effect of 20 (S)-protopanaxadiol on cytochrome P450: potential of its pharmacokinetic interactions in vivo. Biomed Pharmacother 2022;153:113514. 
  63. Balayssac D, Authier N, Cayre A, Coudore F. Does inhibition of P-glycoprotein lead to drug-drug interactions. Toxicol Lett 2005;156:319-29.  https://doi.org/10.1016/j.toxlet.2004.12.008
  64. 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:e98717. 
  65. Zhang J, Zhou F, Niu F, Wu X, Sun J, Wang G. 20(S)-ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo : a case for herb-drug interactions. Drug Metabol Dispos 2010;38:2179-87.  https://doi.org/10.1124/dmd.110.034793
  66. Yang LQ, Wang B, Gan H, Fu ST, Zhu XX, Wu ZN, Zhan DW, Gu RL, Dou GF, Meng ZY. Enhanced oral bioavailability and antitumor effect of paclitaxel by 20(S)-ginsenoside Rg3 in vivo. Biopharmaceuticals and Drug Position 2012;33:425-36.  https://doi.org/10.1002/bdd.1806
  67. Yang Z, Wang JR, Niu T, Gao S, Yin T, You M, Jiang ZH, Hu M. Inhibition of P-glycoprotein of compound K, an anticancer metabolite of red ginseng extract produced by gut microflora. Drug Metabol Dispos 2012;40:1538-44.  https://doi.org/10.1124/dmd.111.044008
  68. Li N, Wang D, Ge G, Wang X, Liu Y, Yang L. Ginsenoside metabolites inhibit P-glycoprotein in vivo and in situ using three absorption models. Planta Med 2014;80:290-6.  https://doi.org/10.1055/s-0033-1360334
  69. Xiong J, Yuan H, Fei S, Yang S, You M, Liu L. The preventive role of the red ginseng ginsenoside Rg3 in the treatment of lung tumorigenesis induced by benzo(a) pyrene. Sci Rep 2023;13:4528. 
  70. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang CY. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Therapeut 2002;72:276-87.  https://doi.org/10.1067/mcp.2002.126913
  71. Anderson GD, Rosito G, Mohustsy MA, Elmer GW. Drug interaction potential of soy extract and Panax ginseng. J Clin Pharmacol 2003;43:643-8.  https://doi.org/10.1177/0091270003253636
  72. 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
  73. Kim DS, Kim Y, Jeon JY, Kim MG. Effect of Red Ginseng on cytochrome P450 and P-g lycoprotein activities in healthy volunteers. J Ginseng Res 2016;40:375-81.  https://doi.org/10.1016/j.jgr.2015.11.005
  74. 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
  75. Park JD. Antitumor activities of Korean ginseng as a health food based upon underlying mechanisms of ginsenosides. In: Chemistry of koran foods and beverages, ACS symposium series. Washington, DC: American Chemical Society; 2019. p. 149-68. 
  76. Bilgi N, Bell K, Ananthakrishnan AN, Atallah E. Imatinib and Panax ginseng: a potential interaction resulting in liver toxicity. Ann Pharmacother 2010;44:926-8.  https://doi.org/10.1345/aph.1M715
  77. Collado-Borrell R, Escudero-Vilaplana V, Romero-Jimenez R, Iglesias-Peinado I, Herranz-Alonso A, Sanjurjo-Saez M. Oral antineoplastic agent interactions with medicinal plants and food: an issue to take into account. J Cancer Res Clin Oncol 2016;142:2319-30.  https://doi.org/10.1007/s00432-016-2190-8
  78. Park J, Song H, Kim SK, Lee MS, Rhee DK, Lee Y. Effects of ginseng on two main sex steroid hormone receptors: estrogen and androgen receptors. J Ginseng Res 2017;41:215-21.  https://doi.org/10.1016/j.jgr.2016.08.005
  79. King ML, Adle SR, Murphy LL. Extraction-dependent effects of American ginseng (Panax quinquefolium) on human breast cancer cell proliferation and estrogen receptor activation. Integr Cancer Ther 2006;5:236-43.  https://doi.org/10.1177/1534735406291341
  80. Hsu WL, Tsai YT, Wu CT, Lai JN. The prescription pattern of Chinese herbal products containing ginseng among tamoxifen-treated female breast cancer survivors in Taiwan: a population-based study. Evid Based Complement Alternat Med 2015:385204. 
  81. Cui Y, Shu XO, Ga YT, Cai H, Tao MH, Zheng W. Association of ginseng use with survival and quality of life among breast cancer patients. Am J Epidemiol 2006;163:645-53.  https://doi.org/10.1093/aje/kwj087
  82. Janetzky K, Morreale AP. Probable interaction between warfarin and ginseng. Am J Health Syst Pharm : AJHP : Official Journal of the American Society of HealthSystem Pharmacists 1997;54:692-3.  https://doi.org/10.1093/ajhp/54.6.692
  83. Jiang X, Williams KM, Liauw WS, Ammit AJ, Roufogalis BD, Duke CC, Day RO, McLachlan AJ. Effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2004;57:592-9.  https://doi.org/10.1111/j.1365-2125.2003.02051.x
  84. Lee YH, Lee BK, Choi YJ, Yoon IK, Chang BC, Gwak HS. Interaction between warfarin and Korean red ginseng in patients with cardiac valve replacement. Int J Cardiol 2010;145:275-6.  https://doi.org/10.1016/j.ijcard.2009.09.553
  85. Lee SH, Ahn YM, Ahn SY, Doo HK, Lee BC. Interaction between warfarin and Panax ginseng in ischemic stroke patients. J Alternative Compl Med 2008;14:715-21. 2008.  https://doi.org/10.1089/acm.2007.0799
  86. Elmer GW, Lafferty WE, Tyree PT, Lind BK. Potential interactions between complementary/alternative products and conventional medicines in a Medicare population. Ann Pharmacother 2007;41:1617-24.  https://doi.org/10.1345/aph.1K221
  87. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2001;286:208-16.  https://doi.org/10.1001/jama.286.2.208
  88. Takahashi M, Tokuyama S. Pharmacological and physiological effects of ginseng on actions induced by opioids and psychostimulants. Methods Find Exp Clin Pharmacol 1998;20:77-84.  https://doi.org/10.1358/mf.1998.20.1.485635
  89. Mitra SK, Chakraborti A, Bhattacharya SK. Neuropharmacological studies on Panax ginseng. Indian J Exp Biol 1996;34:41-7. 
  90. Mateo-Carrasco H, Galvez-Contrertas MC, Fernandez-Gines FD, Nguyen TV. Elevated liver enzymes resulting from interaction between Raltegravir and Panax ginseng : a case report and brief review. Drug Metabol Drug Interact 2012;27:171-5.  https://doi.org/10.1515/dmdi-2012-0019
  91. Bhargava HN, Ramarao P. The effect of Panax ginseng on the development of tolerance to the pharmacological actions of morphine in the rat. Gen Pharmacol 1991;22:521-5.  https://doi.org/10.1016/0306-3623(91)90017-Z
  92. Kim HC, Shin EJ, Jang CG, Lee MK, Eun JS, Hong JT, Oh KW. Pharmacological action of Panax ginseng on the behavioral toxicities induced by psychotropic agents. Arch Pharm Res (Seoul) 2005;28:995-1001.  https://doi.org/10.1007/BF02977391
  93. Abebe W. Herbal medication: potential for adverse interactions with analgesic drugs. J Clin Pharm Therapeut 2002;27:391-401.  https://doi.org/10.1046/j.1365-2710.2002.00444.x
  94. Kiefer D, Pantuso T. Panax ginseng. Am Fam Physician 2003;68:1539-42. 
  95. Seo SH, Park GK, Park JD. Korean ginseng and diabetes: an insight into antidiabetic effects of Korean ginseng(Panax ginseng C. A. Meyer) in cultured cells, animal models and human studies. Korean J Pharmacogn 2020;51:1-29. 
  96. Kim SJ, Choi S, Kim M, Park C, Kim GL, Lee SO, Kang W, Rhee DK. Effect of Korean red ginseng extracts on drug-drug interaction. J Ginseng Res 2018;42:370-8.  https://doi.org/10.1016/j.jgr.2017.08.008
  97. Jeon JH, Lee S, Lee W, Jin S, Kwon M, Shin CH, Choi MK, Song IS. Herb-drug interaction of red ginseng extract and ginsenoside Rc with valsartan in rats. Molecules 2020;25:622. https://doi.org/10.3390/molecules25030622.