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http://dx.doi.org/10.1016/j.jgr.2017.04.011

Gut microbiota-mediated pharmacokinetics of ginseng saponins  

Kim, Dong-Hyun (Department of Life and Nanopharmaceutical Sciences and Department of Pharmacy, College of Pharmacy, Kyung Hee University)
Publication Information
Journal of Ginseng Research / v.42, no.3, 2018 , pp. 255-263 More about this Journal
Abstract
Orally administered ginsengs come in contact with the gut microbiota, and their hydrophilic constituents, such as ginsenosides, are metabolized to hydrophobic compounds by gastric juice and gut microbiota: protopanxadiol-type ginsenosides are mainly transformed into compound K and ginsenoside Rh2; protopanaxatriol-type ginsenosides to ginsenoside Rh1 and protopanaxatriol, and ocotillol-type ginsenosides to ocotillol. Although this metabolizing activity varies between individuals, the metabolism of ginsenosides to compound K by gut microbiota in individuals treated with ginseng is proportional to the area under the blood concentration curve for compound K in their blood samples. These metabolites such as compound K exhibit potent pharmacological effects, such as antitumor, anti-inflammatory, antidiabetic, antiallergic, and neuroprotective effects compared with the parent ginsenosides, such as Rb1, Rb2, and Re. Therefore, to monitor the potent pharmacological effects of ginseng, a novel probiotic fermentation technology has been developed to produce absorbable and bioactive metabolites. Based on these findings, it is concluded that gut microbiota play an important role in the pharmacological action of orally administered ginseng, and probiotics that can replace gut microbiota can be used in the development of beneficial and bioactive ginsengs.
Keywords
fermentation; ginseng; ginsenoside; gut microbiota; metabolism;
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1 Wakabayashi C, Hasegawa H, Murata J, Saiki I. In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. Oncol Res 1998;9:411-7.
2 Hasegawa H, Lee KS, Nagaoka T, Tezuka Y, Uchiyama M, Kadota S, Saiki I. Pharmacokinetics of ginsenoside deglycosylated by intestinal bacteria and its transformation to biologically active fatty acid esters. Biol Pharm Bull 2000;23:298-304.   DOI
3 Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93.   DOI
4 Kennedy DO, Scholey AB. Ginseng: potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav 2003;75:687-700.   DOI
5 Scaglione F, Ferrara F, Dugnani S, Falchi M, Santoro G, Fraschini F. Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drug Exp Clin Res 1990;16:537-42.
6 Singh VK, Agarwhal SS, Gupta BM. Immunomodulatory activity of Panax ginseng extract. Planta Med 1984;50:462-5.   DOI
7 Matsuda H, Namba K, Fukuda S, Tani T, Kubo M. Pharmacological study on Panax ginseng C.A. Meyer. IV. Effects of red ginseng on experimental disseminated intravascular coagulation. (3). Effect of ginsenoside-Ro on the blood coagulative and fibrinolytic system. Chem Pharm Bull 1986;34:2100-4.   DOI
8 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.   DOI
9 Xie JT, Mehendale SR, Li X, Quigg R, Wang X, Wang CZ, Wu JA, Aung HH, Rue PA, Bell GI, et al. Anti-diabetic effect of ginsenoside Re in ob/ob mice. Biochim Biophys Acta 2005;1740:319-25.   DOI
10 Yim JS, Kim YS, Moon SK, Cho KH, Bae HS, Kim JJ, Park EK, Kim DH. Metabolic activities of ginsenoside Rb1, baicalin, glycyrrhizin and geniposide to their bioactive compounds by human intestinal microflora. Biol Pharm Bull 2004;27:1580-3.   DOI
11 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.   DOI
12 Kim DH. Herbal medicines are activated by intestinal microflora. Nat Prod Sci 2002;8:35-43.
13 Kim DH. Gut microbiota-mediated drug-antibiotic interactions. Drug Metab Dispos 2015;43:1581-9.   DOI
14 Kim DH. The possible role of intestinal microflora in pharmacological activities of ginseng. Int Biomed Pharmaceut Sci 2012;6:90-6.
15 Kim DH. Chemical diversity of Panax ginseng, Panax quinquefolius, and Panax notoginseng. J Ginseng Res 2012;36:1-15.   DOI
16 Mikov M. The metabolism of drugs by the gut flora. Eur J Drug Metab Pharmacokinet 1994;19:201-7.   DOI
17 Sousa T, Paterson R, Moore V, Carlsson A, Abrahamsson B, Basit AW. The gastrointestinal microbiota as a site for the biotransformation of drugs. Int J Pharm 2008;363:1-25.   DOI
18 Kobashi K, Akao T. Relation of intestinal bacteria to pharmacological effects of glycosides. Biosci Microflora 1987;16:1-7.
19 Lee J, Lee E, Kim DH, 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.   DOI
20 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.   DOI
21 Hasegawa H, Sung JH, Matsumiya S, Uchiyama M. Main ginseng metabolites formed by intestinal bacteria. Planta Med 1996;62:453-5.   DOI
22 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 1990;38:2859-61.   DOI
23 Odani T, Tanizawa H, Takino Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. II. The absorption, distribution and excretion of ginsenoside Rg1 in the rat. Chem Pharm Bull 1983;31:292-8.   DOI
24 Strombom J, Sandberg F, Dencker L. Studies on absorption and distribution of ginsenoside Rg1 by whole-body autoradiobiography and chromatography. Acta Pharmaceut Suecica 1985;22:113-22.
25 Park EK, Shin YW, Lee HU, Kim SS, Lee YC, Lee BY, Kim DH. Inhibitory effect of ginsenoside Rb1 and compound K on NO and prostaglandin E2 biosyntheses of RAW264.7 cells induced by lipopolysaccharide. Biol Pharm Bull 2005;28:652-6.   DOI
26 Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, Knight R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci USA 2010;107:11971-5.   DOI
27 Tamura G, Gold C, Ferro-Luzzi A, Ames BN. Fecalase: a model for activation of dietary glycosides to mutagens by intestinal flora. Proc Natl Acad Sci USA 1980;77:4961-5.   DOI
28 Kobashi K, Nakata H, Takebe H, Terasawa K. Relation of intestinal microflora to Syo. Wakan-iyaku-kaishi 1984;1:166-7.
29 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.
30 Fanaro S, Chierici R, Guerrini P, Vigi V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl 2003;91:48-55.
31 Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science 2005;308:1635-8.   DOI
32 Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature 2012;489:220-30.   DOI
33 Han BH, Park MH, Han YN, Woo LK, Sankawa U, Yahara S, Tanaka O. Degradation of ginseng saponins under mild acidic conditions. Planta Med 1982;44:146-9.   DOI
34 Kato H, Shimada F, Yano S, Kanaoka M. Determination of ginsenoside Rb1 in plasma of human after intake of red ginseng powder. In: Abstract of papers, 11th Symposium of the Medical Society for Red Ginseng Research, Kobe, Japan; 1990. p. 36 [abstract].
35 Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutri 2000;130:2073S-85S.   DOI
36 Anufriev VP, Malinovskaya GV, Denisenko VA, Uvarova NI, Elyakov GB, Kim SI, Baek NI. Synthesis of ginsenoside Rg3, a minor constituent of ginseng radix. Carbohydr Res 1997;304:179-82.   DOI
37 Park JD, Lee YH, Kim SI. Ginsenoside Rf2, a new dammarane glycoside from Korean red ginseng (Panax ginseng). Arch Pharm Res 1998;21:615-7.   DOI
38 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 2004;27:61-7.   DOI
39 Kown SW, Han SB, Park IH, Kim JM, Park MK, Park JH. Liquid chromatographic determination of less polar ginsenosides in processed ginseng. J Chromatogr A 2001;921:335-9.   DOI
40 Taniyasu S, Tanaka O, Yang TR, Zhou J. Dammarane saponins of flower buds of Panax notoginseng (sanchi-ginseng). Planta Med 1982;44:124-5.   DOI
41 Yu HS, Zhang LJ, Song XB, Liu YX, Zhang J, Cao M, Kang LP, Kang TG, Ma BP. Chemical constituents from processed rhizomes of Panax notoginseng. Zhongguo Zhong Yao Za Zhi 2013;38:3910-7 [In Chinese].
42 Zeng J, Cui XM, Zhou JM, Jiang ZY, Zhang XM, Chen JJ. Studies on chemical constituents from rhizomes of Panax notoginseng. Zhong Yao Cai 2007;30:1388-91.
43 Zhou J, Wu MZ, Taniyasu S, Besso H, Tanaka O, Saruwatari Y, Fuwa T. Dammarane-saponins of sanchi-ginseng, roots of Panax notoginseng (BURK.) F.H. CHEN (Araliaceae): structures of new saponins, notoginsenosides-R1 and -R2, and identification of ginsenosides-$Rg_{2}$ and $-Rh_{1}$. Chem Pharm Bull 1981;29:2844-50.   DOI
44 Park EK, Choo MK, Kim EJ, Han MJ, Kim DH. Antiallergic activity of ginsenoside Rh2. Biol Pharm Bull 2003;26:1581-4.   DOI
45 Chang YS, Seo EK, Gyllenhaal C, Block KI. Panax ginseng: a role in cancer therapy? Integr Cancer Therap 2003;2:13-33.   DOI
46 Helms S. Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev 2004;9:259-74.
47 Choo MK, Park EK, Han MJ, Kim DH. Antiallergic activity of ginseng and its ginsenosides. Planta Med 2003;69:518-22.   DOI
48 Park EK, Choo MK, Han MJ, Kim DH. Ginsenoside Rh1 possesses antiallergic and anti-inflammatory activities. Int Arch Allergy Immunol 2004;133:113-20.   DOI
49 Kim ND, Kang SY, Kim MJ, Park JH, Schini-Kerth VB. The ginsenoside Rg3 evokes endothelium-independent relaxation in rat aortic rings: role of $K^{+}$ channels. Eur J Pharmacol 1999;367:51-7.   DOI
50 Park EK, Choo MK, Oh JK, Ryu JH, Kim DH. Ginsenoside Rh2 reduces ischemic brain injury in rats. Biol Pharm Bull 2004;27:433-6.   DOI
51 Banskota AH, Tezuka Y, Le Tran Q, Kadota S. Chemical constituents and biological activities of Vietnamese medicinal plants. Curr Top Med Chem 2003;3:227-48.   DOI
52 Shieh PC, Tsao CW, Li JS, Wu HT, Wen YJ, Kou DH, Cheng JT. Role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the action of ginsenoside Rh2 against beta-amyloid-induced inhibition of rat brain astrocytes. Neurosci Lett 2008;434:1-5.   DOI
53 Su X, Pei Z, Hu S. Ginsenoside Re as an adjuvant to enhance the immune response to the inactivated rabies virus vaccine in mice. Int Immunopharmacol 2014;20:283-9.   DOI
54 Lee EJ, Ko E, Lee J, Rho S, Ko S, Shin MK, Min BI, Hong MC, Kim SY, Bae H. Ginsenoside Rg1 enhances CD4(+) T-cell activities and modulates Th1/Th2 differentiation. Int Immunopharmacol 2004;4:235-44.   DOI
55 Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012;13:260-70.   DOI
56 Li CP, Li RC. An introductory note to ginseng. Am J Chin Med 1973;1:249-61.   DOI
57 Kim DH. Metabolism of ginsenosides to bioactive compounds by intestinal microflora and its industrial application. J Ginseng Res 2009;33:165-76.   DOI
58 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.   DOI
59 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.   DOI
60 Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH. Metabolism of ginsenoside Rc and its related antiallergic activity. Biol Pharm Bull 2002;25:743-7.   DOI
61 Shibata S, Tanaka O, Nagai M, Ishii T. Studies on the constituents of Japanese and Chinese crude drugs. XII. Panaxadiol, a sapogenin of ginseng roots. Chem Pharm Bull 1963;11:762-5.   DOI
62 Chen CF, Chiou WF, Zhang JT. Comparison of the pharmacological effects of Panax ginseng and Panax quinquefolium. Acta Pharmacol Sin 2008;29:1103-8.   DOI
63 Ng TB. Pharmacological activity of sanchi ginseng (Panax notoginseng). J Pharm Pharmacol 2006;58:1007-19.   DOI
64 Garriques SS. On panaquilon, a new vegetable substance. Ann Chem Pharm 1954;90:231-4.
65 Shibata S, Ando T, Tanaka O, Meguro Y, Soma K, Iida Y. Saponins and sapogenins of Panax ginseng C.A. Meyer and some other Panax spp. Yakugaku Zasshi 1965;85:753-5 [In Japanese].
66 Shibata S, Tanaka O, Soma K, Ando T, Iida Y, Nakamura H. Studies on saponins and sapogenis of ginseng. The structure of panaxatriol. Tetrahedron Lett 1965;42:207-13.
67 Baek SH, Bae ON, Park JH. Recent methodology in ginseng analysis. J Ginseng Res 2012;36:119-34.   DOI
68 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.   DOI
69 Shin HY, Lee JH, Lee JY, Han YO, Han MJ, Kim DH. Purification and characterization of ginsenoside Ra-hydrolyzing beta-D-xylosidase from Bifidobacterium breve K-110, a human intestinal anaerobic bacterium. Biol Pharm Bull 2003;26:1170-3.   DOI
70 Park SY, Bae EA, Sung JH, Lee SK, Kim DH. Purification and characterization of ginsenoside Rb1-metabolizing beta-glucosidase from Fusobacterium K-60, a human intestinal anaerobic bacterium. Biosci Biotechnol Biochem 2001;65:1163-9.   DOI
71 Bae EA, Shin JE, Kim DH. Metabolism of ginsenoside Re by human intestinal microflora and its estrogenic effect. Biol Pharm Bull 2005;28:1903-8.   DOI
72 Jeong JJ, Van Le TH, Lee SY, Eun SH, Nguyen MD, Park JH, Kim DH. Anti-inflammatory effects of vina-ginsenoside R2 and majonoside R2 isolated from Panax vietnamensis and their metabolites in lipopolysaccharide-stimulated macrophages. Int Immunopharmacol 2015;28:700-6.   DOI
73 Lee SY, Jeong JJ, Le TH, Eun SH, Nguyen MD, Park JH, Kim DH. Ocotillol, a majonoside R2 metabolite, ameliorates 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice by restoring the balance of Th17/Treg cells. J Agric Food Chem 2015;63:7024-31.   DOI
74 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.   DOI
75 Zhao P, Liu YQ, Yang CR. Minor dammarane saponins from Panax notoginseng. Phytochemistry 1996;41:1419-22.   DOI
76 Nguyen MD, Nguyen TN, Kasai R, Ito A, Yamasaki K, Tanaka O. Saponins from Vietnamese ginseng, Panax vietnamensis Ha et Grushv. Collected in central Vietnam. I. Chem Pharm Bull (Tokyo) 1993;41:2010-4.   DOI
77 Nguyen MD, Kasai R, Ohtani K, Ito A, Nguyen TN, Yamasaki K, Tanaka O. Saponins from Vietnamese ginseng, Panax vietnamensis HA et Grushv. Collected in central Vietnam. II. Chem Pharm Bull 1994;42:634-40.   DOI
78 Duc NM, Kasai R, Ohtani K, Ito A, Nham NT, Yamasaki K, Tanaka O. Saponins from Vietnamese ginseng, Panax vietnamensis Ha et Grushv. collected in central Vietnam. III. Chem Pharm Bull (Tokyo) 1994;42:115-22.   DOI
79 Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Disp 2003;31:1065-71.   DOI
80 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.   DOI
81 Shibata S. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J Kor Med Sci 2001;16(Suppl.):S28-37.   DOI
82 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.   DOI
83 Shin YW, Bae EA, Kim SS, Lee YC, Kim DH. Effect of ginsenoside Rb1 and compound K in chronic oxazolone-induced mouse dermatitis. Int Immunopharmacol 2005;5:1183-91.   DOI
84 Lee SJ, Ko WG, Kim JH, Sung JH, Moon CK, Lee BH. Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. Biochem Pharmacol 2000;60:677-85.   DOI
85 Tatsuka M, Maeda M, Ota T. Anticarcinogenic effect and enhancement of metastatic potential of BALB/c 3T3 cells by ginsenoside Rh(2). Jpn J Cancer Res 2001;92:1184-9.   DOI
86 Shin YW, Kim DH. Antipruritic effect of ginsenoside rb1 and compound k in scratching behavior mouse models. J Pharm Sci 2005;99:83-8.   DOI
87 Choo MK, Sakurai H, Kim DH, Saiki I. A ginseng saponin metabolite suppresses tumor necrosis factor-alpha-promoted metastasis by suppressing nuclear factor-kappa B signaling in murine colon cancer cells. Oncol Rep 2008;19:595-600.
88 Cui JF, Bjorkhem I, Eneroth P. Gas chromatographic-mass spectrometric determination of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol for study on human urinary excretion of ginsenosides after ingestion of ginseng preparations. J Chromatogr B Biomed Sci Appl 1997;689:349-55.   DOI
89 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.   DOI
90 Bae EA, Hyun YJ, Choo MK, Oh JK, Ryu JH, Kim DH. Protective effect of fermented red ginseng on a transient focal ischemic rats. Arch Pharm Res 2004;27:1136-40.   DOI
91 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 2002;25:165-9.   DOI
92 Ruan CC, Liu Z, Li X, Liu X, Wang LJ, Pan HY, Zheng YN, Sun GZ, Zhang YS, Zhang LX. Isolation and characterization of a new ginsenoside from the fresh root of Panax ginseng. Molecules 2010;15:2319-25.   DOI
93 Shibata S, Fujita M, Itokawa H, Tanaka O. Studies on the constituents of Japanese and Chinese crude drugs. XI. Panaxadiol, a sapogenin of ginseng roots. Chem Pharm Bull (Tokyo) 1963;11:759-61.   DOI
94 Kitagawa I, Taniyama T, Shibuya H, Noda T, Yoshikawa M. Chemical studies on crude drug processing. V. On the constituents of ginseng radix rubra (2): Comparison of the constituents of white ginseng and red ginseng prepared from the same Panax ginseng root. Yakugaku Zasshi 1987;107:495-505 [In Japanese].   DOI
95 Kitagawa I, Yoshikawa M, Yoshihara M, Hayashi T, Taniyama T. Chemical studies on crude drug precession. I. On the constituents of ginseng radix rubra (1). Yakugaku Zasshi 1983;103:612-22.   DOI
96 Zhu GY, Li YW, Hau DK, Jiang ZH, Yu ZL, Fong WF. Protopanaxatriol-type ginsenosides fromthe root of Panax ginseng. Agric Food Chem 2011;59:200-5.   DOI
97 Besso H, Kasai R, Saruwatari Y, Fuwa T, Tanaka O. Ginsenoside Ra1 and ginsenoside Ra2, new dammarane-saponins of ginseng roots. Chem Pharm Bull 1982;30:2380-5.   DOI
98 Kasai R, Besso H, Tanaka O, Saruwatari YI, Fuwa T. Saponins of red ginseng. Chem Pharm Bull 1983;31:2120-5.   DOI
99 Ryu JH, Park TH, Kim DH, Sohn JM, Kim HM, Park JH. A genuine dammarane glycoside, (20E)-ginsenoside F4 from Korean red ginseng. Arch Pharm Res 1996;19:335-6.   DOI
100 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;62:86-7.   DOI