1. Ginsenoside as a Prodrug:
Effect of its Active Metabolites on
Cancer Metastasis
Wonkwang University
Dept of Pharmacy
Dong-Hwan Sohn
2. Suh SO et al. (2002) Effects of red ginseng upon
postoperative immunity and survival in patients with stage III
gastric cancer. Am J Chin Med. 30(4):483-94.
“ …. This study demonstrated a five-year disease free
survival and overall survival rate that was significantly
higher in patients taking the red ginseng powder during
postoperative chemotherapy versus control (68.2% versus
33.3%, 76.4% versus 38.5%, respectively, p < 0.05). In
spite of the limitation of a small number of patients (n = 42)
42),
these findings suggest that red ginseng powder may help
to improve postoperative survival in these patients. ….”
3. Main Biologically Active Constituents
iologically Constituents:
Saponins ( ~ 31 ea)
4.
5.
6. Poor absorption of ginsenoside from the
intestine : less than 3%
The transformation of ginsenosides by human
intestinal bacteria after oral administration.
Good absorption of active metabolites
7.
8.
9.
10.
11. 21% of human fecal specimens shows no
hydrolyzing potential
potential.
Major intestinal bacteria: Prevotella Oris
30. Fig 1. Mean plasma concentration-time profiles of compound K in rats after intravenous
injection of the drug at 1 (), 2 () and 10 () mg/kg (n = 7). Vertical bars represent
standard deviation
31. Table 1. Pharmacokinetic parameters of compound K after iv injection of various doses to rats (n = 7)a
Parameters 1 mg/kg 2 mg/kg 10 mg/kg
Body weight (g) 270 ± 9.9 284 ± 16.0 262 ± 11.1
t1/2 (min) 222 ± 82.5 298 ± 77.9 224 ± 115
AUC (gmin/ml)b 41.8 ± 28.9 115.6 ± 6.8 486.8 ± 188.2
MRT (min) 81.1 ± 31.8 96.1 ± 54.8 79.9 ± 40.5
CL (ml/min/kg) 31.3 ± 14.8 17.3 ± 1.0 23.1 ± 8.4
Vss (ml/kg)
( g) 2744 ± 2050 1677 ± 1001 1757 ± 750
Ae0-24h (% of dose) 0.008 ± 0.008 0.009 ± 0.002 0.006 ± 0.002
GI24h (% of dose) 26.2 ± 3.2 25.2 ± 10.3 24.4 ± 10.4
aValues expressed as mean ± SD.
bDose-normalized (1 mg/kg) AUCs were compared by statistical analysis.
32. Fig 2. Mean plasma concentration-time profiles of compound K in rats after oral
administration of the drug at 5 (, n = 7), 10 (, n = 8) and 20 (, n = 10) mg/kg.
Vertical bars represent standard deviation
33. T bl 2. Pharmacokinetic parameters of compound K after oral administration of various doses to ratsa
Table 2 Ph ki i f d f l d i i i f i d
Parameters 5 mg/kg (n=7) 10 mg/kg (n=8) 20 mg/kg (n=10)
Body weight (g) 245 ± 14.6 254 ± 18.4 224 ± 11.5
AUC (gmin/ml)b 4.50 ± 3.86 21.0 ± 28.8 341.0 ± 201.8c
Tmax (min)
( ) 124 ± 162 191 ± 196 151 ± 122
Cmax (g/ml)b 0.028 ± 0.023 0.078 ± 0.098 0.726 ± 0.386c
Ae0-24h (% of dose) BDd BDd BDd
GI24h (% of dose) 54.3 21.5
54 3 ± 21 5 81.7 26.8
81 7 ± 26 8 77.5 15.3
77 5 ± 15 3
F (%) 1.8 4.3 35.0
aValuesexpressed as mean ± SD.
bDose normali ed
Dose-normalized (5 mg/kg) AUCs were compared by statistical analysis
analysis.
c20 mg/kg was significantly different (p<0.05) from 5 and 10 mg/kg.
34. M t b li
Metabolism of M1
f
Enhancement of antitumor effect of M1 by fatty-acid
esterification
35.
36.
37.
38.
39.
40.
41. Summary
The transformation of ginsenosides by human intestinal
bacteria after oral administration.
Good absorption of active metabolites
21% of human fecal specimens shows no hydrolyzing
potential.
potential
Inhibitory effect by oral adminstration of M1 on tumor
metastasis
Association of Antimetastastic effect of Rb1 with bacterial
Rb1 hydrolyzing
Rb1-hydrolyzing potentials
42. Acknowledgements
The late Dr. Hideo Hasegawa (Fermenta Herb Institute Japan)
Dr Institute,
The late Prof. Emeritus Kim, Jaebaek (Wonpharm. Co. Ltd., Korea)
Dr Lee Hye-Sook (Catholic Univ Korea)
Dr. Lee, Univ.,
